Single-beat evaluation of right ventricular contractility.
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Animals↗
Biomedical subjects
Robert Naeije
Publications and source records attributed to Robert Naeije.
Respiratory muscle strength may explain hypoxia-induced decrease in vital capacity.
PURPOSE: High altitude exposure has consistently been reported to decrease forced vital capacity (FVC), but the mechanisms accounting for this observation remain incompletely understood. We investigated the possible contribution of a hypoxia-related decrease in respiratory muscle strength. METHODS: Maximal inspiratory and expiratory pressures (MIP and MEP), sniff nasal inspiratory pressure (SNIP), FVC, peak expiratory flow rate (PEF), and forced expiratory volume in 1 s (FEV1) were measured in 15 healthy subjects before and after 1, 6, and 12 h of exposure to an equivalent altitude of 4267 m in a hypobaric chamber. RESULTS: Hypoxia was associated with a progressive decrease in FVC (5.59 +/- 0.24 to 5.24 +/- 0.26 L, mean +/- SEM, P < 0.001), MIP (130 +/- 10 to 114 +/- 8 cm H2O, P < 0.01), MEP (201 +/- 12 to 171 +/- 11 cm H2O, P < 0.001), and SNIP (125 +/- 7 to 98 +/- 7 cm H2O, P < 0.001). MIP, MEP, and SNIP were strongly correlated to FVC (r ranging from 0.77 to 0.92). FEV1 didn't change, and PEF increased less than predicted by the reduction in air density (11-20% of sea-level value compared with 32% predicted). CONCLUSION: We conclude that a decrease in respiratory muscle strength may contribute to the decrease in FVC observed at high altitude.
Adult↗
Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease.
Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate. However, 5-10% of patients with advanced COPD may suffer from severe pulmonary hypertension and present with a progressively downhill clinical course because of right heart failure added to ventilatory handicap. The prevalence of clinically significant severe pulmonary hypertension in COPD is roughly estimated to be of 1-2/1,000. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathologic studies point rather at extensive remodeling of all layers of the pulmonary arterial walls. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacologic treatment of pulmonary hypertension in selected patients with advanced COPD and right heart failure. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive patients with COPD.
Antihypertensive Agents↗
Current perspectives modern hemodynamic evaluation of the pulmonary circulation. Application to pulmonary arterial hypertension and embolic pulmonary hypertension.
The hemodynamic evaluation of the pulmonary circulation normally includes the measurements of mean pulmonary artery pressure and a calculation of pulmonary vascular resistance (PVR). The definition of PVR can be improved by the measurements of pulmonary vascular pressures at several levels of flow to derive a pressure-flow line, and the site of PVR can be identified by the analysis of pulmonary artery pressure decay curves after balloon occlusion. An analysis of the morphology of pulmonary artery pressure and flow waves informs about right ventricular (RV) hydraulic load. As pulmonary hypertension is clinically a right heart failure syndrome, it is important to measure the coupling of RV to pulmonary arterial function. This can be done using a single beat method with sampling and synchronization of instantaneous pulmonary artery flow and RV pressure to calculate a ratio of end-systolic to arterial elastances. The optimal value of this ratio is depressed in minimally symptomatic pulmonary arterial hypertension patients, indicating pending right heart failure.
Blood Flow Velocity↗
Chemoreflex and metaboreflex control during static hypoxic exercise.
To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 +/- 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O(2)) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated (P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia (P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.
Adult↗
Signaling molecules in overcirculation-induced pulmonary hypertension in piglets: effects of sildenafil therapy.
BACKGROUND: The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II. CONCLUSIONS: Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.
3',5'-Cyclic-GMP Phosphodiesterases↗
Increased sympathetic nerve activity in pulmonary artery hypertension.
BACKGROUND: This study tested the hypothesis that sympathetic nerve activity is increased in pulmonary artery hypertension (PAH), a rare disease of poor prognosis and incompletely understood pathophysiology. We subsequently explored whether chemoreflex activation contributes to sympathoexcitation in PAH. METHODS AND RESULTS: We measured muscle sympathetic nerve activity (MSNA) by microneurography, heart rate (HR), and arterial oxygen saturation (Sao(2)) in 17 patients with PAH and 12 control subjects. The patients also underwent cardiac echography, right heart catheterization, and a 6-minute walk test with dyspnea scoring. Circulating catecholamines were determined in 8 of the patients. Chemoreflex deactivation by 100% O(2) was assessed in 14 patients with the use of a randomized, double-blind, placebo-controlled, crossover study design. Compared with the controls, the PAH patients had increased MSNA (67+/-4 versus 40+/-3 bursts per minute; P<0.0001) and HR (82+/-4 versus 68+/-3 bpm; P=0.02). MSNA in the PAH patients was correlated with HR (r=0.64, P=0.006), Sao(2) (r=-0.53, P=0.03), the presence of pericardial effusion (r=0.51, P=0.046), and NYHA class (r=0.52, P=0.033). The PAH patients treated with prostacyclin derivatives had higher MSNA (P=0.009), lower Sao(2) (P=0.01), faster HR (P=0.003), and worse NYHA class (P=0.04). Plasma catecholamines were normal. Peripheral chemoreflex deactivation with hyperoxia increased Sao(2) (91.7+/-1% to 98.4+/-0.2%; P<0.0001) and decreased MSNA (67+/-5 to 60+/-4 bursts per minute; P=0.0015), thereby correcting approximately one fourth of the difference between PAH patients and controls. CONCLUSIONS: We report for the first time direct evidence of increased sympathetic nerve traffic in advanced PAH. Sympathetic hyperactivity in PAH is partially chemoreflex mediated and may be related to disease severity.
Calcium Channel Blockers↗
Sildenafil for enhanced performance at high altitude?
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3',5'-Cyclic-GMP Phosphodiesterases↗
Serotonin in pulmonary arterial hypertension.
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Animals↗
Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension.
The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an evidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reviewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the level of evidence of treatments based on the number of favorable controlled clinical trials performed with a given compound is adopted; a treatment algorithm based on the evidence derived by clinical trials is proposed. It includes drugs approved by regulatory agencies for the treatment of patients with PAH and/or drugs available on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments have been evaluated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intravenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who have failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.
Algorithms↗
Endogenous angiotensin II in the regulation of hypoxic pulmonary vasoconstriction in anaesthetized dogs.
INTRODUCTION: The role played by several vasoactive mediators that are synthesized and released by the pulmonary vascular endothelium in the regulation of hypoxic pulmonary vasoconstriction (HPV) remains unclear. As a potent vasoconstrictor, angiotensin II could be involved. We tested the hypothesis that angiotensin-converting enzyme inhibition by enalaprilat and type 1 angiotensin II receptor blockade by candesartan would inhibit HPV. METHODS: HPV was evaluated in anaesthetized dogs, with an intact pulmonary circulation, by examining the increase in the Ppa-Ppao gradient (mean pulmonary artery pressure minus occluded pulmonary artery pressure) that occurred in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow. Plasma renin activity and angiotensin II immunoreactivity were measured to determine whether activation or inhibition of the renin-angiotensin system was present. RESULTS: Administration of enalaprilat and candesartan did not affect the Ppa-Ppao gradient at baseline or during hypoxia. Plasma renin activity and angiotensin II immunoreactivity increased during hypoxia, and subsequent measurements were consistent with effective angiotensin-converting enzyme inhibition after administration of enalaprilat, and with angiotensin receptor blockade after administration of candesartan. CONCLUSION: These results suggest that, although the renin-angiotensin system was activated in hypoxia, angiotensin II is not normally involved in mediating acute HPV.
Angiotensin II↗
Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology.
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Arterial Occlusive Diseases↗
Isoflurane and desflurane impair right ventricular-pulmonary arterial coupling in dogs.
BACKGROUND: Halogenated anesthetics depress left ventricular function, but their effects on the right ventricle have been less well studied. Therefore, the authors studied the effects of isoflurane and desflurane on pulmonary arterial (PA) and right ventricular (RV) properties at baseline and in hypoxia. METHODS: Right ventricular and PA pressures were measured by micromanometer catheters, and PA flow was measured by an ultrasonic flow probe. PA mechanics were assessed by flow-pressure relations and by impedance spectra derived from flow and pressure waves. RV contractility was assessed by end-systolic elastance (Ees), RV afterload was assessed by effective PA elastance (Ea), and RV-PA coupling efficiency was assessed by the Ees:Ea ratio. Anesthetized dogs were randomly assigned to increasing concentrations (0.5, 1, and 1.5 times the minimum alveolar concentration) of isoflurane (n = 7) or desflurane (n = 7) in hyperoxia (fraction of inspired oxygen, 0.4) and hypoxia (fraction of inspired oxygen, 0.1). RESULTS: Isoflurane and desflurane had similar effects. During hyperoxia, both anesthetics increased PA resistance and characteristic impedance, increased Ea (isoflurane, from 0.82 to 1.44 mmHg/ml; desflurane, from 0.86 to 1.47 mmHg/ml), decreased Ees (isoflurane, from 1.09 to 0.66 mmHg/ml; desflurane, from 1.10 to 0.72 mmHg/ml), and decreased Ees:Ea (isoflurane, from 1.48 to 0.52; desflurane, from 1.52 to 0.54) in a dose-dependent manner (all P < 0.05). Hypoxia increased PA resistance, did not affect characteristic impedance, increased afterload, and increased contractility. During hypoxia, isoflurane and desflurane had similar ventricular effects as during hyperoxia. CONCLUSIONS: Isoflurane and desflurane markedly impair RV-PA coupling efficiency in dogs, during hyperoxia and hypoxia, both by increasing RV afterload and by decreasing RV contractility.
Anesthetics, Inhalation↗
Effects of norepinephrine and dobutamine on pressure load-induced right ventricular failure.
OBJECTIVE: A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects norepinephrine and dobutamine on RV-PA coupling in this model of RV failure. DESIGN: Prospective, controlled, randomized animal study. SETTING: University research laboratory. SUBJECTS: Twenty-two anesthetized dogs. INTERVENTIONS: Animals underwent transient (90-min) PA constriction to induce persistent RV failure. They were randomly assigned to control, norepinephrine, or dobutamine group. Norepinephrine was administered at 0.1 and 0.5 microg x kg x min or dobutamine at 5 and 10 microg x kg x min. MEASUREMENTS AND MAIN RESULTS: We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We also measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. The transient PA constriction persistently increased PA resistance and elastance, increased Ea from 0.8+/-0.1 to 2.7+/-0.3 mmHg/mL, decreased Ees from 1.1+/-0.1 to 0.5+/-0.1 mm Hg/mL, and decreased Ees/Ea from 1.2+/-0.1 to 0.2+/-0.1. Norepinephrine restored arterial pressure, increased RV contractility, and increased but did not normalize RV-PA coupling and cardiac output. Dobutamine restored arterial pressure, markedly increased RV contractility, and normalized RV-PA coupling and cardiac output. Compared with norepinephrine, dobutamine decreased PA resistance and elastance and increased RV contractility and RV-PA coupling. CONCLUSIONS: A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Dobutamine restores RV-PA coupling and cardiac output better than norepinephrine because of its more pronounced inotropic effect.
Animals↗
Prevention of hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction by N-acetylcysteine in dogs.
We investigated the possible contributions of reactive oxygen species and of viscosity changes to hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction (HPV) in dogs. Fourteen isoflurane-anesthetized dogs were randomly assigned to receive N-acetylcysteine (NAC) 200 mg/kg IV (n = 7) or placebo (n = 7). Mean pulmonary artery pressure (Ppa) was measured with cardiac output maintained constant by a manipulation of venous return in hyperoxia (fraction of inspired oxygen, 0.4) and in hypoxia (fraction of inspired oxygen, 0.1) at baseline and after stepwise reductions in hematocrit from 40% to 20%. Measured Ppa was compared with predicted Ppa by using a viscoelastic model. HPV was expressed as hypoxic Ppa minus hyperoxic Ppa. Hemodilution was associated with a decrease in HPV from 7 +/- 1 mm Hg to 3 +/- 1 mm Hg (P < 0.01), and this was completely prevented by NAC (HPV was unchanged, from 8 +/- 1 to 8 +/- 1 mm Hg; not significant). Hemodilution in the model decreased HPV from 8 +/- 1 mm Hg to 6 +/- 1 mm Hg (P < 0.05). We conclude that hemodilution-induced inhibition of HPV is in part explained by viscosity changes and can be prevented by the administration of NAC, which is possibly explained by the scavenging of reactive oxygen species.
Acetylcysteine↗
Feasibility of routine pulmonary arterial impedance measurements in pulmonary hypertension.
OBJECTIVES: Right ventricular (RV) afterload is best described by a pulmonary arterial impedance (PVZ) spectrum, which integrates pulmonary vascular resistance (PVR), elastance, and wave reflection. We evaluated the feasibility of PVZ determinations in patients with pulmonary arterial hypertension (PAH) during routine right heart catheterization and Doppler echocardiography. DESIGN: Prospective study. SETTING: Academic hospital. PATIENTS: Twenty-two patients with PAH. INTERVENTIONS: Right heart catheterization with a fluid-filled Swan-Ganz catheter, Doppler echocardiography, and administration of inhaled nitric oxide (NO) [10 to 20 ppm; 17 patients], maximum tolerated dose of IV epoprostenol (average, 8.5 ng/kg/min; 5 patients), and IV dobutamine (8 micro g/kg/min; 8 patients). MEASUREMENTS AND RESULTS: PVZ was calculated from the spectral analysis of synchronized pulmonary artery pressure (Ppa) and flow waves. The mean (+/- SE) Ppa was 63 +/- 3 mm Hg, and the mean PVR was 16 +/- 2 Wood units. The PVZ spectrum was markedly shifted to higher than normal pressures and frequencies, with a mean 0-Hz impedance (Z(0)) of 1,506 +/- 138 dyne. s. cm(-5), and a mean characteristic impedance (Zc) of 124 +/- 11 dyne. s. cm(-5), which are in keeping with data from previous studies. Inhaled NO levels decreased Ppa, PVR, Z(0), and Zc without a change in cardiac output. Epoprostenol administration did not affect Ppa, increased cardiac output, and decreased Z(0) and Zc. Dobutamine administration increased cardiac output and Ppa, and decreased PVR and Z(0), without changing Zc. CONCLUSIONS: The determination of PVZ to quantify RV afterload is feasible during routine right heart catheterization and Doppler echocardiography. The measurement is sensitive to pharmacologic interventions.
Adult↗
Treprostinil for pulmonary hypertension.
Treprostinil (Remodulin, United Therapeutics) is a stable, long-acting prostacyclin analog, which has been shown to improve clinical state, functional class, exercise capacity and quality of life in patients with pulmonary arterial hypertension, an uncommon disease with poor prognosis. The drug is administered as a continuous subcutaneous infusion using a portable miniature delivery system. Side effects include facial flush, headache, jaw pain, abdominal cramping and diarrhea. These are all typical of prostacyclin impregnation and manageable by symptom-directed dose adjustments. Infusion site pain, a more serious side effect, may limit the treatment in 10% of patients. Otherwise, treprostinil has an excellent safety profile and compares favorably with reference continuous intravenous epoprostenol (Flolan, GlaxoSmithKline) therapy. Treprostinil has a place in currently proposed treatment algorithms of pulmonary arterial hypertension.
Antihypertensive Agents↗
Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension.
BACKGROUND: Pulmonary thromboendarterectomy (PTE) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but persistent pulmonary hypertension after PTE, as a result of either inaccessible distal thrombotic material or coexistent intrinsic small-vessel disease, remains a major determinant of poor outcome. Conventional preoperative evaluation is unreliable in identifying patients at risk for persistent pulmonary hypertension or predicting postoperative hemodynamic outcome. We postulated that pulmonary arterial occlusion pressure waveform analysis, a technique that has been used for partitioning pulmonary vascular resistance, might identify CTEPH patients with significant distal, small-vessel disease. METHODS AND RESULTS: Twenty-six patients underwent preoperative right heart catheterization before PTE. Pulmonary artery occlusion waveform recordings were performed in triplicate. Postoperative hemodynamics after PTE were compared with preoperative partitioning of pulmonary vascular resistance derived from the occlusion data. Preoperative assessment of upstream resistance (Rup) correlated with both postoperative total pulmonary resistance index (R2=0.79, P<0.001) and postoperative mean pulmonary artery pressure (R2=0.75, P<0.001). All 4 postoperative deaths occurred in patients with a preoperative Rup <60%. CONCLUSIONS: Pulmonary arterial occlusion pressure waveform analysis may identify CTEPH patients at risk for persistent pulmonary hypertension and poor outcome after PTE. Patients with CTEPH and Rup value <60% appear to be at highest risk.
Adult↗