Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow

2007 ◽  
Vol 292 (6) ◽  
pp. H3006-H3018 ◽  
Author(s):  
Zahra Ghorishi ◽  
Jay M. Milstein ◽  
Francis R. Poulain ◽  
Anita Moon-Grady ◽  
Theresa Tacy ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Shear Stress ◽  
High Resistance ◽  
Vascular Reactivity ◽  
Fractal Model ◽  
Pulmonary Hemodynamic ◽  
Pulmonary Arterial ◽  
Hemodynamic Reactivity ◽  
And Control

Congenital heart disease with increased blood flow commonly leads to the development of increased pulmonary vascular reactivity and pulmonary arterial hypertension by mechanisms that remain unclear. We hypothesized a shear stress paradigm of hemodynamic reactivity and network remodeling via the persistence and/or exacerbation of a fetal diameter bifurcation phenotype [parent diameter d0and daughters d1≥ d2with α < 2 in ( d1/ d0)α+ ( d2/ d0)αand area ratio β < 1 in β = ( d12+ d22)/ d02] that mechanically acts as a high resistance magnifier/shear stress amplifier to blood flow. Evidence of a hemodynamic influence on network remodeling was assessed with a lamb model of high-flow-induced secondary pulmonary hypertension in which an aortopulmonary graft was surgically placed in one twin in utero (Shunt twin) but not in the other (Control twin). Eight weeks after birth arterial casts were made of the left pulmonary arterial circulation. Bifurcation diameter measurements down to 0.010 mm in the Shunt and Control twins were then compared with those of an unoperated fetal cast. Network organization, cumulative resistance, and pressure/shear stress distributions were evaluated via a fractal model whose dimension D0≈ α delineates hemodynamic reactivity. Fetus and Control twin D0differed: fetus D0= 1.72, a high-resistance/shear stress amplifying condition; control twin D0= 2.02, an area-preserving transport configuration. The Shunt twin ( D0= 1.72) maintained a fetal design but paradoxically remodeled diameter geometry to decrease cumulative resistance relative to the Control twin. Our results indicate that fetal/neonatal pulmonary hemodynamic reactivity remodels in response to shear stress, but the response to elevated blood flow and pulmonary hypertension involves the persistence and exacerbation of a fetal diameter bifurcation phenotype that facilitates endothelial dysfunction/injury.

Alterations in Endogenous Nitric Oxide Production After Cardiopulmonary Bypass in Lambs With Normal and Increased Pulmonary Blood Flow

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
D. Michael McMullan ◽  
Janine M. Bekker ◽  
Andrew J. Parry ◽  
Michael J. Johengen ◽  
Alexander Kon ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Cardiopulmonary Bypass ◽  
Pulmonary Blood Flow ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
No Production ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
Nitrite Nitrate

Background —After cardiopulmonary bypass (CPB), altered vascular reactivity is a major source of complications, particularly for children with increased pulmonary blood flow. Although changes in agonist-induced NO activity are well described after CPB, potential changes in basal NO production and their role in post-CPB pulmonary hypertension remain unclear. By using aortopulmonary vascular graft placement in the fetal lamb (shunt lambs), we established a unique model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. The objective of the present study was to investigate potential alterations in endogenous NO production after CPB in lambs with normal and increased pulmonary blood flow. Methods and Results —Vascular pressures and blood flows were monitored in 1-month-old lambs (n=7) with increased pulmonary blood flow and 6 age-matched control lambs. After shunt closure, hypothermic CPB (25°C) was performed for 2 hours. The hemodynamic variables were monitored for 4 hours after CPB. Before, during, and after CPB, peripheral lung biopsies were performed to determine tissue NO, nitrite, nitrate, and cGMP concentrations; total NO synthase (NOS) activity; and endothelial NOS protein levels. Hypothermic CPB increased both mean pulmonary arterial pressure and left pulmonary vascular resistance ( P <0.05). The increase in pulmonary arterial pressure induced in shunt lambs was greater than that induced in control lambs ( P <0.05). Four hours after CPB, tissue concentrations of NO, nitrite, nitrate, and cGMP were decreased to ≈70% of pre-CPB levels in both control and shunt lambs ( P <0.05). Total NOS activity and endothelial NOS protein levels were unchanged. Conclusions —Modest decreases in basal NO production, the inability to increase NO production, or both may play a role in the altered pulmonary vascular reactivity after CPB. The decrease in NO is independent of gene expression. However, other mechanisms for this decrease, such as substrate or cofactor availability, warrant further study.

The response of the pulmonary circulation to exercise during normoxia and hypoxia following pneumonectomy in the adult sheep

1989 ◽  
Vol 67 (3) ◽  
pp. 202-206 ◽  
Author(s):  
Michele Smith ◽  
Geoffrey Coates ◽  
J. Michael Kay ◽  
Hugh O'Brodovich
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Hemodynamic Response ◽  
Pulmonary Hemodynamics ◽  
Vascular Reserve ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Hemodynamic ◽  
Pulmonary Arterial ◽  
Increased Blood Flow

Pneumonectomy approximately halves the available pulmonary vascular bed. It is unknown whether the remaining lung has sufficient vascular reserve to cope with increased blood flow under stressful conditions without demonstrating abnormal pulmonary hemodynamics. To investigate this question, unanesthetized ewes with vascular catheters had hemodynamics assessed before and after a left pneumonectomy. Subsequently, on different days, the sheep were exercised on a treadmill under normoxic and hypobaric hypoxic (430 mmHg) (1 mmHg = 133.3 Pa) conditions. Pneumonectomy itself increased mean pulmonary arterial pressure by 4 mmHg. During normoxic or hypoxic exercise, the pneumonectomized sheep demonstrated a pulmonary hemodynamic response similar to normal sheep with two lungs. The pressure–flow relation for the right lung suggested the vascular reserve of the lung was not exceeded during exercise in the pneumonectomized sheep. Eighteen to 70 days after pneumonectomy there was no evidence of right ventricular hypertrophy, but there were small increases in the number of muscularized vessels less than 50 μm diameter and in the amount of muscle in normally muscularized pulmonary arteries. This study demonstrates that pneumonectomy slightly increases mean pulmonary arterial pressure. However, there is sufficient vascular reserve in the remaining lung to permit a normal hemodynamic response to exercise-induced increased blood flow even under hypoxic conditions.Key words: pulmonary hypertension, pneumonectomy, sheep.

The Influence of Pulmonary Hemodynamics on Right Ventricular Function in Pulmonary Hypertension

2013 ◽  
Author(s):  
Vitaly O. Kheyfets ◽  
Lourdes Rios ◽  
Triston Smith ◽  
Theodore Schroeder ◽  
Jeffrey Mueller ◽  
...  
Keyword(s):  
Fluid Dynamics ◽  
Pulmonary Hypertension ◽  
Shear Stress ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Pulmonary Hemodynamics ◽  
Arterial Hemodynamics ◽  
Computational Fluid Dynamics Cfd ◽  
Pulmonary Arterial ◽  
Rv Function

Pulmonary arterial hypertension (PAH) is a degenerative disease that can lead to substantial morphometric remodeling of the pulmonary arteries. Previous studies have revealed coupling relationships between right ventricular (RV) function and pulmonary arterial hemodynamics. The objective of this study was to utilize computational fluid dynamics (CFD) to estimate spatially averaged Wall Shear Stress (WSS) for patients with PH and explore correlations between hemodynamics metrics and RV function.

Pulmonary vascular reactivity in hyperoxic pulmonary hypertension in the rat

1988 ◽  
Vol 65 (6) ◽  
pp. 2617-2623 ◽  
Author(s):  
R. G. Gore ◽  
R. Jones
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Reactivity ◽  
Normal Lung ◽  
Base Line ◽  
Alveolar Wall ◽  
Ang Ii ◽  
Pulmonary Vascular Remodeling ◽  
Perfused Lung ◽  
Pulmonary Arterial ◽  
Line Resistance

Breathing 87% O2 for 7 days causes pulmonary vascular remodeling and pulmonary hypertension in the rat. In the isolated perfused lung of the normal and O2-exposed rat, change in pre- and postcapillary resistance was determined in response to challenge with angiotensin II (ANG II; 5, 25, and 50 micrograms) or histamine (0.5 and 1.0 microgram). In the hyperoxic lung both pre- and postcapillary resistance were increased at base line, although the latter less consistently so. In response to each agent precapillary resistance increased more than postcapillary resistance in the hyperoxic lung. In the normal lung pre- and postcapillary reactivity to histamine were similar but the latter was the greater in response to ANG II. In the hyperoxic lung only the pre- and postcapillary response to the first challenge of ANG II (5 micrograms) was greater than normal. The magnitude of the precapillary response was not related to the level of base-line resistance, and this response was significantly increased in a small number of hyperoxic lungs with base-line resistance in the normal range. Tachyphylaxis occurred after the first dose of ANG II. In the hyperoxic lung only the precapillary response to 0.5 micrograms histamine was greater than normal. We conclude that exposure to hyperoxia for 7 days causes an increase in pulmonary arterial reactivity. Furthermore, the alteration in reactivity is not caused by vascular restriction. We hypothesize that it is attributable to peripheral extension of smooth muscle in alveolar wall arteries.

Pulmonary hypertension induced by repeated pulmonary inflammation in the rat

1981 ◽  
Vol 51 (3) ◽  
pp. 755-761 ◽  
Author(s):  
J. Herget ◽  
F. Palecek ◽  
P. Preclik ◽  
M. Cermakova ◽  
M. Vizek ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pulmonary Hypertension ◽  
Lung Inflammation ◽  
Pulmonary Inflammation ◽  
Control Group ◽  
Arterial Blood ◽  
The Media ◽  
Pulmonary Arterial ◽  
The Mean ◽  
And Control

The effect of repeated lung inflammation on the pulmonary vascular bed was studied in rats. Nonbacterial lung inflammation was induced by repeated carrageenan instillations into the lungs. Three days after the single carrageenan injection, the mean pulmonary arterial blood pressure was only slightly raised [16.3 +/- 0.6 (mean +/- SE) Torr in controls and 19.5 +/- 0.5 Torr in rats with lung inflammation, P less than 0.001]. A substantial pulmonary hypertension was found in rats 3 days after the sixth lung inflammation (24.6 +/- 1 Torr). In this group, arterial hypoxemia, hypercapnia, and right-heart hypertrophy were found. In the 14th day of recovery after the last injection of carrageenan, the mean pulmonary artery blood pressure decreased (18.5 +/- 0.9 Torr) but remained higher than in the control group. There was no difference in cardiac output measured by dye-dilution technique between the experimental and control groups. After repeated inflammation, the media of distal pulmonary vessels thickened and the number of pulmonary arterioles with distinct media increased.

Abstract 2305: Pulmonary Vascular Reactivity And Prognosis In Patients With Chronic Thromboembolic Pulmonary Hypertension

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nika Skoro-Sajer ◽  
Nicklas Hack ◽  
Roela Sadushi ◽  
Johannes Jakowitsch ◽  
Diana Bonderman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Mean Pulmonary Arterial Pressure ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Relative Change

Hemodynamic responder status defined as an acute decrease of mean pulmonary arterial pressure (mPAP)>10mmHg and below 40mmHg is associated with improved outcome in patients (pts) with pulmonary arterial hypertension (PAH). Pulmonary vascular reactivity to nitric oxide (NO) is controversial in chronic thromboembolic pulmonary hypertension (CTEPH). We speculated that the magnitude of the acute decrease in mean pulmonary artery pressure (mPAP) after exposure to NO might reflect the degree of small vessel disease in CTEPH and thus, affect long-term outcome. Methods: Right heart catheterization was performed in 62 (55  ± 15 years, 32 female) pts with major-vessel CTEPH, at baseline and during inhalation of 40ppm NO. Within 25±15 days patients underwent pulmonary endarterectomy (PEA). Pts were followed for 11.3±26 months. Predictors of survival were analyzed by Cox regression analysis, and survival was described by Kaplan-Meier curves. Results: Significant reductions in mean pulmonary arterial pressure (mPAP; p<0.001), pulmonary vascular resistance (PVR; p<0.001) and an increase in mixed venous oxygen saturation following NO inhalation were demonstrated (p<0.001) by a paired t-test. Stepwise multivariate analysis revealed the relative change of PVR after NO inhalation as a predictor of survival. Patients whose PVR during NO inhalation declined below 789.8 dynes.s.cm-5 had significantly better outcome than patients with above median PVR. There was a strong negative correlation between the relative change of PVR under NO and recurrent pulmonary hypertension after PEA (p=0.02). Conclusions: Patients with operable CTEPH demonstrated acute pulmonary vascular reactivity, mostly not corresponding to a complete responder status, but accounting for a wide range of decreases of mPAP [change of mPAP (%) (−10.9±14)] and PVR [change of PVR (%) (−17 ±15)]. Reduction of PVR under 800 dynes.s.cm-5 after inhalation of NO was associated with better outcome. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with CTEPH undergoing PEA.

Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude

1988 ◽  
Vol 65 (6) ◽  
pp. 2632-2640 ◽  
Author(s):  
R. F. Grover ◽  
R. L. Johnson ◽  
R. G. McCullough ◽  
R. E. McCullough ◽  
S. E. Hofmeister ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Sea Level ◽  
Vascular Reactivity ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Prostaglandin Synthesis ◽  
Inhibition Of Prostaglandin Synthesis ◽  
Pulmonary Arterial ◽  
Low Altitude

It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.

scholarly journals Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

1997 ◽  
Vol 6 (5-6) ◽  
pp. 323-326 ◽  
Author(s):  
A. Serraf ◽  
J-P. Gascard ◽  
J. Bruniaux ◽  
C. Labat ◽  
C. Planche ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Congenital Heart Defects ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Heart Defects ◽  
Blood Levels ◽  
Blood Samples ◽  
Number Of Patients ◽  
Pulmonary Arterial

The circulating levels of leukotriene E4in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56 ± 4 mmHg) and the leukotriene E4levels (1.37 ± 0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4blood levels in the small number of patients studied.

Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension

1998 ◽  
Vol 275 (5) ◽  
pp. H1643-H1651 ◽  
Author(s):  
Stephen M. Black ◽  
Jeffrey R. Fineman ◽  
Robin H. Steinhorn ◽  
James Bristow ◽  
Scott J. Soifer
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Vascular Reactivity ◽  
Heart Defects ◽  
Pulmonary Arteries ◽  
Enos Gene ◽  
Rnase Protection

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart defects and increased pulmonary blood flow. Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity. The objective of this study was to characterize potential early alterations in expression, localization, and activity of endothelial NO synthase (eNOS) induced by increased pulmonary blood flow and pulmonary hypertension. Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Ten fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blotting were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. eNOS mRNA (2.4:1, P < 0.05) and protein (2.08:1, P < 0.05) were increased in lungs of shunt lambs. In situ hybridization and immunohistochemistry revealed that the increase was confined to the endothelium of pulmonary arteries. eNOS protein (1.55:1, P < 0.05) and tissue cGMP concentrations (2.1:1, P < 0.05) were also increased in isolated fifth-generation pulmonary arteries of shunt lambs. In addition, total lung eNOS activity was increased (2.9:1, P < 0.05). Thus we report a previously undescribed, early upregulation of eNOS gene expression and activity in lambs with increased pulmonary blood flow and pulmonary hypertension.

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