Pulmonary Vascular Resistance Response Research Articles

Acute vasoreactivity testing for severe pulmonary hypertension associated with lung disease

Abstract Background Pulmonary hypertension results in clinical deterioration and increases mortality risk in patients with lung disease (LD), including chronic obstructive pulmonary disease, interstitial lung disease and combined pulmonary fibrosis and emphysema. Though acute vasoreactivity testing predicts long term-survival of patients with pulmonary arterial hypertension (PAH), its clinical impact for patients with pulmonary hypertension associated with LD (LD-PH) remains unknown. Purpose The purpose of this study is to clarify the clinical impact of acute vasoreactivity testing using inhaled nitric oxide for severe LD-PH. Methods We retrospectively reviewed 65 consecutive patients with LD-PH between January 2014 and December 2022; 48 patients (73 [68–78] years; males, 81%; median follow-up period 23 [7–35] months) with severe pulmonary hypertension who underwent acute vasoreactivity testing were included. We divided the patients based on a median pulmonary vascular resistance (PVR) response (−15%) in acute vasoreactivity testing into the high-responder (PVR response ≦−15%) and the low-responder (PVR response >−15%) groups. Results Acute vasoreactivity testing significantly decreased mean pulmonary arterial pressure (mPAP) (from 41 [34–48] to 36 [31–40] mmHg, P<0.01) and PVR (from 10.7 [8.3–13.8] to 8.9 [6.6–11.4] Wood units, P<0.01). The high-responder group had better long-term survival than the low-responder group (P = 0.03). Univariate Cox regression analysis showed that the prognostic factors for better survival included younger age, high-responder to acute vasoreactivity testing, and PAH-specific therapy (P <0.01, 0.04, 0.03, respectively). There were correlations between the PVR response at acute vasoreactivity testing and improvement in mPAP (R=0.40, P=0.03) or PVR (R = 0.47, P <0.01) with PAH-specific therapy. Conclusions PVR response at acute vasoreactivity testing was associated with better long-term survival and haemodynamic improvement with PAH-specific therapy. Acute vasoreactivity testing may be useful to predict the responders to PAH-specific therapy and long-term survival in patients with severe LD-PH.

Phosphodiesterase 9A inhibition improves aging-related increase in pulmonary vascular resistance in mice.

As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a 3-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11 dyn s cm-5 (21% and 57% increase, P=0.01 and P<0.0001). The PVR response to PROP was amplified at HA to 76% (P<0.0001, P[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (P<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2% mmHg-1 with PROP+GLYC (P=0.01). Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions.

Pulmonary hemodaynamic in obesity

Abstract Background Higher prevalence of pulmonary hypertension exist in obesity subjects. Little known about pulmonary hemodynamics during exercise in obesity population. Purpose To assess and compare the response of pulmonary vascular resistance during exercise in obese subjects vs healthy controls. Methods Seventeen obesity subjects (gender: 25%men, age: 44±11 years, height: 1.7±0.1 m, weight: 111±17 kilogram, BMI: 38±4 kg/m2) were compared to twenty gender-, age-, height- and race-matched healthy control subjects (age: 46±12 years, height: 1.7±0.1 m, weight: 64±11 kilogram, BMI: 22±2 kg/m2). All subjects underwent an incremental exercise stress echocardiography with measurements of pulmonary artery pressure (PAP), cardiac output (CO), cardiac index (CI) and tricuspid annular plane systolic excursion (TAPSE) at rest and at increasing exercise intensities. Total pulmonary vascular resistance index (PVRi) was calculated as mean PAP/CI and right ventricular-arterial coupling as TAPSE/systolic PAP. Results The results are described in the table 1. Pulmonary hemodynamic was not different at rest between two groups, but lower at maximal exercise in obesity subjects. In obesity subjects, identical exercise level was associated with a higher mean PAP and PVRi, and a lower TAPSE/systolic PAP ratio. Conclusion While pulmonary hemodynamic seems preserved at rest in obesity patients, pulmonary vascular resistance is increased and right ventricular coupling is decreased, particularly at exercise. Funding Acknowledgement Type of funding source: None

Pulmonary vascular disease in swine with multiple comorbidities

IntroductionDiabetes mellitus (DM), chronic kidney disease (CKD) and hypercholesterolemia are common co‐morbidities associated with low‐grade inflammation and endothelial dysfunction leading to increased systemic vascular resistance, diastolic dysfunction and exercise intolerance. Diastolic dysfunction is a risk factor for development of post‐capillary pulmonary hypertension (PH), which, in a subgroup of patients, deteriorates into combined pre‐and post‐capillary PH. This process is characterized by an increase in pulmonary vascular resistance (PVR) due to pulmonary vascular dysfunction and remodeling. It is incompletely understood which factors predispose to the development of combined pre‐and post‐capillary PH. We hypothesize that comorbidities cause pulmonary endothelial dysfunction, which in turn initiates pulmonary vascular remodeling, increases PVR and further reduces exercise tolerance.ObjectiveTo investigate the contribution of endothelial dysfunction, characterized by perturbances in the nitric oxide (NO)‐cGMP‐phosphodiesterase 5 (PDE5) pathway, to changes in PVR at rest and during exercise in a swine model with multiple co‐morbidities.MethodsDM (streptozotocin 3×50mg/kg iv) and CKD (renal embolization) were induced in 6 female swine fed a high fat diet (DM+HFD+CKD), while 8 female healthy swine on normal diet served as controls (CON). Six months later, swine were chronically instrumented and hemodynamics were studied at rest and during exercise, in the absence and presence of eNOS‐inhibition (LNNA, 20 mg/kg iv) and PDE5‐inhibition (sildenafil, 100 mg iv).ResultsDM+HFD+CKD swine exhibited hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min), and inflammation (TNF‐α 51.6±5.1 vs 24.6±5.5pg/ml, all P&lt;0.05).DM+HFD+CKD swine had similar pulmonary arterial pressures at rest and during exercise compared to CON swine, while cardiac index was significantly reduced, reflecting the higher PVR in DM+HFD+CKD. DM+HFD+CKD swine showed a similar increase in PVR in response to eNOS‐inhibition compared to CON swine at rest and during exercise. However, PDE5 inhibition resulted in a significant reduction in PVR, reflecting pulmonary vasodilation in CON, but not in DM+HFD+CKD swine. Altogether, these data suggest that impaired PDE5‐activity acts to preserve the vasodilator effect of endogenous NO in DM+HFD+CKD.ConclusionsExposure to multiple co‐morbidities in a swine model causes an increase in inflammatory factors, which is accompanied by a reduced activity in the NO‐pathway, that is counterbalanced by reduction in PDE5‐activity in swine with DM+HFD+CKD. Hence, exposure to co‐morbidities causes pulmonary endothelial dysfunction and an increase in PVR, even in the absence of overt PH. Thus, pulmonary vascular disease might be an underestimated contributing factor in the disease progress in patients with multiple co‐morbidities and diastolic dysfunction.Support or Funding InformationFunding: CVON‐RECONNECTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The responses of pulmonary and systemic circulation and airway to anaphylactic mediators in anesthetized BALB/c mice

AimsAnaphylactic shock sometimes accompanies pulmonary vaso- and broncho-constriction. We previously reported the hemodynamic features of mouse anaphylaxis (Life Sci. 2014; 116: 98–105). However, the effects of anaphylactic chemical mediators on the hemodynamics of in vivo mice are not well known. Furthermore, it is uncertain whether the mediators exert the same directional actions. Therefore, we determined their effects systematically on total peripheral resistance (TPR), pulmonary vascular resistance (PVR), or airway pressure (AWP) in anesthetized mice. Main methodsWe measured directly pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, central venous pressure and aortic blood flow to determine PVR and TPR, as well as AWP, following injections of platelet-activating factor (PAF), histamine, serotonin, leukotriene (LT) C4, and prostaglandin (PG) D2 in anesthetized open-chest artificially ventilated BALB/c mice. Key findingsConsecutive administration of any agents increased PVR dose-dependently with the maximal responsiveness being PAF>LTC4>serotonin>>histamine=PGD2. Histamine caused a biphasic PVR response, an initial decrease, which was abolished by L-NAME, followed by an increase at high doses. PAF, serotonin, and histamine decreased TPR dose-dependently, while LTC4 or PGD2 yielded an increase or no change in TPR, respectively. Serotonin, but not the other agents, increased AWP. SignificanceAnaphylactic mediators exert non-uniform actions on the pulmonary and systemic circulation and airway in anesthetized BALB/c mice: PAF, LTC4 and serotonin cause substantial pulmonary vasoconstriction, while histamine biphasic responses of the initial nitric oxide dependent vasodilation followed by vasoconstriction; PAF, serotonin, and histamine, but not LTC4 or PGD2, evoke systemic vasodilatation; only serotonin induces airway constriction.

Sodium Nitroprusside in Patients With Mixed Pulmonary Hypertension and Left Heart Disease: Hemodynamic Predictors of Response and Prognostic Implications

BackgroundMixed pulmonary hypertension (PH) in heart failure (HF) is defined by transpulmonary gradient ≥ 12 and/or pulmonary vascular resistance (PVR) ≥ 240 dyne/s/cm−5, but diastolic pressure gradient (DPG) ≥ 7 mmHg has been proposed more recently. We evaluated the acute hemodynamic response to sodium nitroprusside (SNP) specifically in relation to the proposed DPG criterion ≥7 mmHg and the prognostic significance of response to SNP in patients with mixed PH and advanced HF. MethodsNinety-eight consecutive patients with advanced HF and mixed PH underwent cardiac catheterization and acute SNP infusion. Baseline hemodynamic parameters included transpulmonary gradient, PVR, DPG, and pulmonary capacitance (PCap). Hemodynamic response to SNP was defined as a reduction in PVR of at least 20%. The composite endpoint was death/heart transplantation/mechanical circulatory support. ResultsSixty of the 98 patients were SNP responders. SNP resulted in significant reductions in filling pressures and PVR and increase in stroke volume and PCap. DPG (not baseline PVR) was significantly associated with hemodynamic response to SNP on logistic regression analysis. The sensitivity and specificity of a DPG ≥7 mmHg to identify nonresponders to SNP were 74% and 97%, respectively. At median follow-up of 218 (148–324) days, 13 and 19 patients of the SNP responders and nonresponders, respectively, met the composite endpoint (P = .021 by log-rank test). Hemodynamic response to SNP and PCap were independently associated with the composite outcome of survival free from transplantation/mechanical circulatory support. ConclusionBaseline DPG ≥ 7 mmHg is associated with poor PVR response to SNP. PVR response to SNP and PCap are associated with a more favorable prognosis in patients with advanced HF and mixed PH.

PP.32.25

Objective: Pulmonary hypertension (PH) is a group of chronic progressive diseases that have different etiology, but similar clinical presentation. Two conservative ways of treatment are available for such patients: calcium-channel blockers and specific PAH therapy. To define the right strategy right heart catheterization with acute vasodilator test (AVT) is performed. The aim of our study was to analyze the group of «true» responders, non-responders and patients in the «grey zone». Design and method: We analyzed 164 patients with verified diagnosis of PH who underwent right heart catheterization with AVT. Responders met the traditional criteria: reduction at 10 mm Hg. or more in mean pulmonary artery pressure with the aim of 40 mm Hg. and less with no evidence reduction in cardiac output. Non-responders did nit meet any of these criteria, while patients who are neither non-responders nor responders were defined as a “grey zone”. Results: All patients finally were divided into three groups: 34 responders, 28 non-responders and the largest group of 101 patients in a “grey zone”. Among the last group there was a big amount of patients with high reduction in pulmonary vascular resistance (PVR) (24,7 patients with reduction in PVR more than 300 dyn*sec/m2/cm5 with maximum of 1384 dyn*sec/m2/cm5), though they did not meet the criteria of cardiac output or/and mean pulmonary artery pressure. Among these 101 patients there were 26 with chronic thromboembolic pulmonary hypertension, 7 with PH associated with cardiac shunts, 12 with systemic connective tissue diseases and up to 48 of patients with Idiopathic pulmonary hypertension. The amount of patients with a high reduction in PVR (more than 300 dyn*sec/m2/cm5) is 26 with more than a half of patients with idiopathic pulmonary hypertension. Conclusions: In our national register we observed a huge amount of patients, who may present a great reduction in PVR in response to AVT - so called «grey zone». We need more research to specify the strategy for these patients.

Transpulmonary B-Type Natriuretic Peptide Uptake and Cyclic Guanosine Monophosphate Release in Heart Failure and Pulmonary Hypertension: The Effects of Sildenafil

We sought to identify factors that discriminate heart failure (HF) patients with normal and elevated pulmonary vascular resistance (PVR) and to elucidate the role of cyclic guanosine monophosphate (cGMP)-dependent vasodilation. Mechanisms of PVR increase in patients with chronic HF are incompletely understood. Twenty-two HF patients with high pulmonary vascular resistance (H-PVR) (>200 dyn.s.cm(-5)) were compared with 24 matched low pulmonary vascular resistance (L-PVR) patients of similar age, sex, body size, HF severity, and volume status who were undergoing invasive hemodynamic study. Pulmonary arterial (PA) and venous blood samples from a wedged PA catheter were used to calculate transpulmonary B-type natriuretic peptide (BNP) uptake and cGMP release. The H-PVR patients were re-examined 1 h after a 40-mg oral dose of sildenafil. Although transpulmonary BNP uptake was similar (p = 0.2), cGMP release was diminished in the H-PVR patients (-1.9 vs. 27.8 nmol.min(-1); p = 0.005). Transpulmonary BNP uptake and cGMP release correlated in the L-PVR patients (R = 0.6, p = 0.004) but not in the H-PVR. The H-PVR patients also had lower PA compliance, systemic arterial compliance (by 47% and 20%, p < 0.001 and p < 0.03), and cardiac index. Sildenafil reduced PVR (-47%), systemic resistance (-24%) and heart rate (-8%), increased cardiac index (+24%), and PA compliance (+87%, all p < 0.001), with a parallel increase of cGMP release (from -5.6 to 16.5 nmol.min(-1), p = 0.047), without affecting BNP uptake or norepinephrine(PA). The PVR response was not dependent on PA wedge pressure or pulmonary hypertension reversibility with prostaglandin E(1). The H-PVR patients have stiffening of both pulmonary and systemic arteries, preserved transpulmonary BNP uptake, but diminished cGMP release, which is reversible by the administration of sildenafil. This study provides in vivo evidence that phosphodiesterase 5A inhibition restores sensitivity of pulmonary vasculature to endogenous cGMP-dependent vasodilators.

Abstract 14: Pulmonary Hemodynamics in Neonatal Lambs with Pulmonary Hypertension - Effect of Resuscitation with 21% versus 100% Oxygen

The optimal level of O 2 supplementation during neonatal resuscitation is controversial. We recently published data that resuscitation with 21% or 100% O 2 for 30 min results in similar decreases in pulmonary vascular resistance (PVR) in normal newborn lambs ( Pediatr Res in press) . However, the effect of resuscitation with 21% or 100% O 2 on pulmonary hemodynamics in lambs with in-utero pulmonary hypertension (PH) is not known. Methods: PH was induced in fetal lambs by antenatal ductal ligation at 126 d of gestation (term ~ 145 d). Lambs were delivered 9 d later by C-section and ventilated with 21% O 2 or 100% O 2 for 30 min. Control lambs without PH were ventilated similarly for comparison (n=4 −7 in each group). The lambs were instrumented to measure PVR prior to delivery. After 30 min, lambs with PH were ventilated with 50% O 2 and pulmonary vasodilator responses to inhaled NO 20 ppm were evaluated. Results: PVR was significantly higher in lambs with PH compared to control. The decrease in PVR was similar by 30 min in 21% and 100% O 2 resuscitated control lambs. In contrast, 100% O 2 resuscitation resulted in a significantly greater decrease in PVR in lambs with PH (fig A ). However, 100% O 2 resuscitation impaired subsequent decrease in PVR in response to inhaled NO in both control and PH lambs (fig B ). Conclusions: 100% O 2 resuscitation results in a greater decrease in PVR but impairs subsequent pulmonary vasodilation to NO in lambs with PH. Speculation: Ventilation of PH lambs with 100% O 2 significantly increases lung isoprostane levels ( AJRCCM 2006 174 12:1370 ). We speculate that a similar increase in reactive oxygen species following 100% O 2 resuscitation interferes with the vasodilator response to NO.

Pulmonary response to 3h of hypoxia in prone pigs

Studies in whole animals, isolated lungs and pulmonary tissue strips have shown that the pulmonary vascular resistance (PVR) to hypoxia is temporally biphasic in nature. We studied the regional temporal response to hypoxia in prone pigs. The animals were ventilated with an FIO2 of 0.21 (control), followed by an FIO2 of 0.12 for 180 min. A biphasic response in P(pa) to hypoxia was seen with the first peak between 10 and 20 min and a second rise in P(pa) starting after 30 min, which was due to an increase in cardiac output. Regional blood flow (Q ) and ventilation (V (A)) were measured using i.v. infusion of 15 microm and inhalation of 1 microm fluorescent microspheres, respectively. We grouped the lung pieces according to their temporal relative flow response to hypoxia. The five groups were each spatially distributed similarly, but not identically, among the animals. The corresponding relative ventilation to each group did not vary much. We conclude that in the prone pig, the PVR response to sustained hypoxia varies among regions of the lungs. Following an initial rise in PVR in most lung pieces, we found unexpectedly that some regions continue to increase PVR progressively and while other regions decrease PVR after the initial increase. The net effect is little change of overall PVR to hypoxia with time. Normoxic control animals had little change in their hemodynamics and the large majority of the lung pieces did not change their resistance over 3h. We speculate that the differential response of regions may be due to a differential role of nitric oxide, endothelin-1 release or K(+) channels.

Nitric Oxide in the Evaluation of Congenital Heart Disease with Pulmonary Hypertension: Factors Related to Nitric Oxide Response

Inhaled nitric oxide (NO) has been used in the preoperative evaluation of patients with congenital heart disease and pulmonary hypertension. The purpose of this study was to characterize responses in pulmonary vascular resistance (PVR) to oxygen and increasing doses of NO during cardiac catheterization and to determine if any related factors affect the response of the pulmonary vascular bed to NO. A prospective analysis of 42 patients (median age, 3.0 years) with congenital heart disease and pulmonary hypertension who underwent NO testing was performed. Systemic vascular resistance (SVR) and PVR were assessed in room air, 100% oxygen, and oxygen plus 20, 40, and 80 parts per million (ppm) NO. Changes in pulmonary artery pressure, PVR, and SVR were assessed. The response to NO was then correlated to individual patient's age, gender, type of heart defect, the presence of trisomy 21, and baseline PVR/SVR. There was a greater decrease in PVR and PVR/SVR with 20 ppm NO than with oxygen alone. There was no additional decrease at 40 or 80 ppm NO. There was no correlation between age, gender, type of congenital heart disease, and baseline PVR/SVR ratio with the degree of response to NO. Patients with trisomy 21 had less of a response to NO (p = 0.017) than patients without trisomy 21. There is no difference in determining PVR response with doses of NO beyond 20 ppm during cardiac catheterization. Age, gender, and baseline PVR/SVR ratio are not associated with responsiveness to NO. Patients with trisomy 21 may be less responsive to NO.

Leukotrienes in Acute Lung Injury

Leukotrienes in Acute Lung Injury

Is the transpulmonary pressure gradient a predictor for mortality after orthotopic cardiac transplantation?

Elevated pulmonary vascular resistance (PVR) is a well-known risk factor for right ventricular failure after orthotopic cardiac transplantation. The influence of preoperative transpulmonary pressure gradient (TPG) and PVR on post-transplant 30 days mortality was evaluated. To analyze the response of PVR and TPG to cardiac transplantation, we analyzed 718 adult patients undergoing primary cardiac transplantation. Indications for operation were: 35.2% ischemic cardiomyopathy (ICM), 61.2% idiopathic dilated cardiomyopathy (DCM), and 3.3% other diagnosis (e.g. hypertrophic cardiomyopathy). The mean age (51.9) and the mean ischemic time (169.7 min) were comparable between 30 days survivors and nonsurvivors. Student's t-tests and chi-square analysis were used to compare data from 30-day survivors and nonsurvivors. Statistical significance was defined as P < 0.05. Fisher's exact test and multiple logistic regression analysis was performed to evaluate the relationship between hemodynamic parameters and outcome after transplantation. Primary end-point was 30 days mortality and secondary end-point long-term survival of patient groups with different TPG and PVR values. In survivors the mean TPG was 10.3 +/- 5.1 (mean +/- SD) vs. 13 +/- 6.6 in patients who died after transplantation (P = 0.0012). The PVR was 2.6 +/- 1.4 vs. 3.5 +/- 2.2 (P = 0.0012). In multivariate logistic regression, the parameters TPG and PVR exhibit a significant influence between survivors and nonsurvivors after cardiac transplantation within 30 days (TPG: P = 0.0012; PVR: P = 0.0012). The mortality rates in patients with TPG > 11 mmHg and PVR < 2.8 Wood units or TPG < 11 mmHg and PVR > 2.8 Wood units were comparable to those with TPG < 11 mmHg and PVR < 2.8 mmHg. The TPG is an important predictor in nonrejection-related early mortality after orthotopic cardiac transplantation. The determination of TPG in combination with PVR is a more reliable predictor of early post-transplant survival than PVR alone.

Evidence for reduced SMAD signalling in diverse forms of pulmonary arterial hypertension (PAH)

Mutations in BMPR2, the gene encoding the type II bone morphogenetic protein receptor (BMPR-II), underlie many cases of primary pulmonary hypertension (PPH). PAH is characterised by an increased pulmonary vascular resistance in response to obliteration of small arteries by myofibroblast and endothelial cell proliferations (lesions). Mutant BMPR2 may disrupt downstream signalling leading to disordered vascular cell differentiation and proliferation. We explored BMPR-II, phosphorylated Smad (pSmad1) and Smad ubiquitination regulatory factor-1 (SMURF1; a Smad inhibitor), expression in PPH and in PAH due to other causes.

The endothelin antagonist BQ123 reduces pulmonary vascular resistance after surgical intervention for congenital heart disease

Objective: Postoperative pulmonary hypertension in children after surgical intervention for congenital heart disease has been attributed to failure of the pulmonary endothelium to provide adequate vasodilation. Although we have shown that the impaired vasodilatory component attributable to the l-arginine-nitric oxide pathway is almost completely reversible, a nonrestorable component persists, implying an additional vasoconstrictive mechanism in postoperative pulmonary endothelial dysfunction. In this study of children after surgical intervention for congenital heart disease, we measured endothelin-1 levels and used BQ123, a selective endothelin-A receptor antagonist, together with inhaled nitric oxide to discriminate dysfunctional pulmonary endothelial vasodilation from endothelin-mediated pulmonary vasoconstriction. Methods: All children were examined early after surgical intervention in the intensive care unit. Pulmonary vascular resistance (with respiratory mass spectrometry), as well as arterial and venous endothelin-1 levels (measured by means of a quantitative enzyme-linked immunosorbent assay), were determined in 7 children (age range, 3.3-13.7 months; median age, 6.3 months) with intracardiac shunting defects at baseline and during ventilation with a fraction of inspired oxygen of 0.65, with additional BQ123 (0.1 mg/kg infused over 20 minutes), and with inhaled nitric oxide (20 ppm). Results: Pulmonary vascular resistance decreased from 7.7 ± 3.4 at baseline to 6.1 ± 2.8 Woods units · m−2 (P =.022) at a fraction of inspired oxygen of 0.65 and to 4.7 ± 2.7 Woods units · m−2 (P =.013) during BQ123 infusion. Inhaled nitric oxide had no further effect on pulmonary vascular resistance. Left atrial endothelin-1 levels (1.35-5.12 pg/mL; mean, 2.4 pg/mL) correlated significantly with the decrease in pulmonary vascular resistance in response to BQ123 infusion (r2 = 0.89, P =.003). Conclusion: Postoperative elevation of pulmonary vascular resistance in children after surgical intervention for congenital heart disease is responsive to endothelin-A blockade with BQ123. Increased levels of endothelin-1 predict the response to this therapy, which might become an important addition to the clinical armamentarium in postoperative pulmonary hypertensive disease.J Thorac Cardiovasc Surg 2002;124:435-41

Oxygen Therapy Improves Cardiac Index and Pulmonary Vascular Resistance in Patients With Pulmonary Hypertension

We tested the hypothesis that breathing 100% oxygen could result in selective pulmonary vasodilatation in patients with pulmonary hypertension, including those patients who would not meet current Health Care Finance Administration guidelines for long-term oxygen therapy. From 1996 to 1999, 23 adult patients (mean +/- SEM age, 51 +/- 4 years) with pulmonary arterial hypertension without left-heart failure underwent cardiac catheterization in a university teaching hospital while breathing air and then 100% oxygen. Treatment with 100% oxygen increased arterial oxygen saturation (91 +/- 1% to 99 +/- 0.1%, p < 0.05) and PaO(2) (64 +/- 3 to 309 +/- 28 mm Hg, p < 0.05). Treatment with 100% oxygen also decreased mean pulmonary artery pressure (56 +/- 3 to 53 +/- 2 mm Hg, p < 0.05) and increased cardiac index (2.1 +/- 0.1 to 2.5 +/- 0.2 L/min/m(2), p < 0.05). Calculated mean pulmonary vascular resistance (PVR) decreased from 14.1 +/- 1.4 to 10.6 +/- 1.0 Wood units (p < 0.05). Vasodilatation with 100% oxygen occurred preferentially in the pulmonary circulation (PVR/systemic vascular resistance, 0.53 +/- 0.04 to 0.48 +/- 0.03; p < 0.05). The magnitude of the PVR response to oxygen therapy was correlated only with decreasing patient age (r = 0.45, p < 0.05). Treatment with 100% oxygen is a selective pulmonary vasodilator in patients with pulmonary hypertension, regardless of primary diagnosis, baseline oxygenation, or right ventricular function. Development of disease-specific oxygen prescription guidelines warrants consideration.

TREATMENT OF PULMONARY HYPERTENSION WITH NITRIC OXIDE IN CARDIAC SURGERY PATIENTS IS ASSOCIATED WITH A HIGHER RVEF AND A LOWER REQUIREMENT FOR PRESSORS COMPARED TO TREATMENT WITH MILRINONE

Introduction: Milrinone is frequently used to treat increased pulmonary vascular resistance (PVR) in the setting of adult cardiac surgery. The role of inhaled nitric oxide (NO) in this setting is currently being elucidated [1]. The goal of this study was to determine whether treatment of pulmonary hypertension with NO after cardiac surgery results in an altered hemodynamic profile or requirement for vasopressor agents when compared to treatment with milrinone. Methods: 45 consenting adult cardiac surgery patients with a history of pulmonary hypertension (PVR>125 dyn[center dot]cm-5 sec) were assigned by random number allocation to one of three study groups: Group 1 patients (n=15) were treated with intravenous milrinone upon separation from cardiopulmonary bypass, Group 2 patients (n=15) with 20 ppm NO, and group 3 (n=15) with 40 ppm NO. An algorithm was established to ensure that the treatment of hemodynamic disturbance was uniform. Data were statistically analyzed using standard ANOVA in conjunction with Student-Newman-Keuls multiple comparison test. Wilcoxon Rank Sum Analysis was used where ANOVA assumptions were not satisfied. A p-value <0.05 was considered significant. Results: There were no significant differences in demographics, anesthesia, surgery, or baseline hemodynamics between the groups. The percent reduction in PVR in response to the therapeutic regimen was statistically similar in the three study groups. There was no significant difference in cardiac index between the three groups at any time. The heart rate of milrinone-treated patients was significantly (P<0.05) higher than patients treated with 20 or 40 ppm of NO post bypass and upon arrival to the ICU (heart rate =103, 92, 94 respectively for the three groups immediately post bypass, and 109, 94, 94 respectively upon ICU arrival). The group receiving 40 ppm NO had a significantly higher (P<0.05) RVEF upon arrival to the ICU (RVEF=40% versus 30% for the milrinone group and 33% for the NO 20 ppm group). The milrinone group required significantly (P<0.05) more phenylephrine in the ICU than either of the NO groups. Discussion: This study demonstrates that treatment of pulmonary hypertension with NO in adult cardiac surgery patients is associated with an equal reduction in PVR, a lower heart rate, and a lower requirement for treatment with pressor agents when compared to treatment with milrinone. The fact that there was no significant difference in cardiac index between groups, and that the RVEF was higher in the group receiving 40 ppm of NO despite equal afterload reduction (% decrease in PVR) remains enigmatic since no intrinsic inotropic property has been previously ascribed to NO.

Changes in pulmonary vascular resistance in response to partial liquid ventilation

Background/Purpose: Partial liquid ventilation (PLV) with perfluorocarbons decreases pulmonary vascular resistance (PVR) in injured piglet lungs without supplemental oxygen. These PVR changes may result either from direct mechanical effects or improved arterial oxygenation. In an uninjured hypoxic model of elevated PVR the authors asked the following questions: (1) Does prophylactic or therapeutic PLV ameliorate the PVR response to hypoxia? (2) Do prophylactic and therapeutic PLV have different PVR effects? (3) Does supplemental oxygen modify PVR response to PLV? Methods: Piglet (3 to 4 kg) lungs were isolated in situ without ischemia, hypoxia, or reperfusion injury. Pulmonary artery (PA) and left atrial (LA) cannulae were attached to a bloodprimed extracorporeal membrane oxygenation (ECMO) perfusion circuit with a flow (Q PA) of 80 mL/kg/min. Pressure-limited, volume-cycled ventilation (PIP < 25 mm Hg, T v = 15 mL/kg) was initiated. PLV with perfluorodecalin (15 mL/kg) was administered endotracheally. Continuously monitored blood gas parameters allowed airway and extracorporeal adjustment of Fio 2 to produce a Po 2 appropriate to the experimental phase. PVR was calculated as ( P PA−P LA Q PA ). After a stable 30-minute normoxic baseline, animals were assigned randomly to three groups. In group I, control (n = 7), PVR was measured for 150 minutes in hypoxic lungs ( Fio 2 = 0.07, P PAo 2 = 40 mm Hg, S PAo 2 = 70%). In group II, prophylactic (n = 8), PLV was administered, followed by 90 minutes of hypoxia, and 60 minutes of oxygen recovery ( Fio 2 = 0.21 – 0.30, P PAo 2 > 100 mm Hg, S PAo 2 = 100%). In group III, therapeutic (n = 8), after 30 hypoxic minutes, PLV was administered and maintained for 90 minutes, followed by a 60-minute oxygen recovery phase. Results were expressed as mean ± SEM. Statistical analysis of groups was performed by repeated measures of analysis of variance (ANOVA) and Tukey correction. Results: In group I normoxic gas-ventilated PVR was 174 ± 12 mm Hg/L/kg/min. After 90 hypoxic minutes PVR was 318 ± 37 ( P < .01 v baseline). In group II baseline PVR was 183 ± 14. PVR after 30 normoxic minutes of PLV was 199 ± 14 ( P = ns v baseline). After 90 hypoxic minutes, PVR was 350 ± 31 ( P < .01 v baseline, and PLV alone) followed by a decrease to 192 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline or PLV alone). In group III baseline PVR was 160 ± 17 and 325 ± 29 after 30 hypoxic minutes. After 90 hypoxic minutes of PLV, PVR was 366 ± 22 ( P = ns v hypoxia control, P < .01 v normoxic baseline). PVR recovered to 189 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline). Conclusions: Prophylactic/therapeutic PLV had no effect on hypoxia-induced increases in PVR and did not differ from each other. Although PLV alone decreases PVR in the injured lung without supplemental oxygen, elevated PVR associated with hypoxia was ameliorated only by supplemental oxygen in the liquid ventilated lung.

Purine nucleotides contribute to pulmonary vasodilation caused by birth-related stimuli in the ovine fetus.

We investigated the hypothesis that the purine nucleotides ATP and adenosine mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We instrumented 44 fetal lambs to measure left pulmonary arterial pressure and flow. In control studies, we investigated the effects of sequential ventilation with 10, 50, and 100% O2 on fetal pulmonary arterial pressure and flow and pulmonary vascular resistance (PVR). We also measured the blood and plasma ATP levels in the pulmonary artery and left atrium in the control studies. In three separate groups of studies, we investigated the effects of 8-phenyltheophylline, an adenosine-receptor antagonist, and cibacron blue, an inhibitor of ATP-sensitive P2y receptors, given alone or in combination, on the response of PVR to sequential ventilation. Fetal arterial PO2 increased during ventilation with 50 and 100% O2 but not with 10% O2. Ventilation with 10% O2 caused a 4-fold increase in pulmonary blood flow and a 10-fold decrease in PVR. Ventilation with 50 and 100% O2 caused a 7-fold increase in pulmonary blood flow and a 20-fold decrease in PVR. Blood and plasma ATP levels in the pulmonary artery and blood ATP levels in the left atrium increased significantly during ventilation with 50 and 100% O2 but not with 10% O2. Pretreatment of animals with 8-phenyltheophylline attenuated the increase in pulmonary flow and decrease in PVR caused by ventilation at all fractions of inspired O2 (FIO2 levels). Pretreatment of animals with cibacron blue attenuated pulmonary vasodilation at 50 and 100% FIO2. Combined treatment with 8-phenyltheophylline and cibacron blue caused complete inhibition of the decrease in PVR in response to ventilation at the three FIO2 levels. Incubation of fetal red blood cells in vitro with 100% O2 caused an increase in ATP production. An increase in arterial PO2 in the fetus causes an increase in blood ATP levels, and an inhibition of ATP receptors attenuates the O2-induced decrease in PVR. Adenosine-receptor inhibition attenuates both ventilation- and O2-induced changes in PVR. Increased synthesis and release of ATP plays a major role in causing pulmonary vasodilation in response to birth-related stimuli in the ovine fetus.