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Find video protocols related to scientific articles indexed in Pubmed.
Dobutamine stress for evaluation of right ventricular reserve in pulmonary arterial hypertension.
Eur. Respir. J.
PUBLISHED: 11-01-2014
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Right ventricular contractile response to pharmacological stress in pulmonary arterial hypertension (PAH) has not been characterised. We evaluated right ventricular contractile reserve in adults with PAH using dobutamine stress echocardiography. 16 PAH patients and 18 age-matched controls underwent low-dose dobutamine stress echocardiography. Contractile reserve was assessed by the change (?; peak stress minus rest value) in tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (S'). A subgroup of 13 PAH patients underwent treadmill cardiopulmonary exercise testing for peak oxygen uptake (V'O2peak). At rest, TAPSE and S' were reduced in the PAH group compared with controls (1.7±0.4 versus 2.4±0.2 cm and 9.7±2.6 cm·s(-1) versus 12.5±1.2 cm·s(-1), respectively; p<0.05). Contractile reserve was markedly attenuated in PAH compared to controls (?TAPSE 0.1±0.2 versus 0.6±0.3 cm and ?S' 4.6±2.8 versus 11.2±3.6 cm·s(-1); p<0.0001). In the sub-group of PAH patients with preserved right ventricular systolic function at rest, contractile reserve remained depressed compared to controls. V'O2peak was significantly correlated with ?S' (r = 0.87, p = 0.0003) and change in stroke volume (r = 0.59, p = 0.03). Dobutamine stress can reveal sub-clinical reduction in right ventricular contractile reserve in patients with PAH. A correlation with exercise capacity suggests potential clinical value beyond resting measurements.
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Pulmonary Arterial Hypertension: The Key Role of Echocardiography.
Echocardiography
PUBLISHED: 09-23-2014
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Echocardiography is a key screening tool in the diagnostic algorithm of pulmonary arterial hypertension (PAH). It provides an estimate of right ventricular function and pulmonary artery pressure, either at rest or during exercise, and is useful in ruling out secondary causes of pulmonary hypertension (PH) such as left heart disease or congenital heart disease. Several studies have showed that echocardiography is insufficiently precise as single tool for the ultimate diagnosis of PH respect to the right heart catheterization, considered the gold standard technique. Echocardiography is valuable in assessing prognosis and treatment options, monitoring the efficacy of specific therapeutic interventions, and detecting the preclinical stages of disease. The ideal imaging modality for accurate noninvasive assessment of the right heart should be accurate and precise, not influenced by loading conditions, routinely practicable and easily repeatable. For all such reasons and considering that PAH is a rare and severe condition, a complete noninvasive assessment of right heart function requires a deep knowledge of the disease and a multimodality approach.
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Right Heart and Pulmonary Vessels Structure and Function.
Echocardiography
PUBLISHED: 09-23-2014
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The right ventricle (RV) can be described in terms of 3 components: the inlet, the apex, and the infundibulum. In the normal adult, the RV shows an arrangement suited for pumping blood against low resistance, with a mass about one sixth that of left ventricle (LV) mass, and a larger volume than the LV. The RV is able to manage a progressive increase in the afterload by increasing contractility and remodeling. The gold standard measurement of contractility is maximal elastance (Emax), or the ratio between end-systolic pressure (ESP) and end-systolic volume (ESV), and the best measurement of afterload is arterial elastance (Ea), or the ratio between ESP and stroke volume (SV). The ratio Emax/Ea defines RV-arterial coupling. The optimal energy transfer from the RV to the pulmonary circulation is measured at Emax/Ea ratios of 1.5-2. In the presence of pulmonary hypertension, the SV/ESV ratio may be an acceptable surrogate of Emax/Ea. The right atrium (RA) has 3 anatomical components: the appendage, the venous part, and the vestibule. It is a dynamic structure having different functions: reservoir, conduit, and booster pump function. In case of increased afterload, the RA is enlarged, denoting high RA pressure, as a consequence of elevated RV diastolic pressure. RA area is a strong predictor of adverse clinical outcome in pulmonary arterial hypertension. In patients with severe pulmonary hypertension, in several congenital heart diseases, and in Eisenmenger syndrome, symptoms and prognosis are greatly dependent on RV function and its ability to adapt to a chronic increase in afterload.
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RV-pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension.
Heart
PUBLISHED: 09-13-2014
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Prognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload.
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Reading pulmonary vascular pressure tracings. How to handle the problems of zero leveling and respiratory swings.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 05-30-2014
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The accuracy of pulmonary vascular pressure measurements is of great diagnostic and prognostic relevance. However, there is variability of zero leveling procedures, and the current recommendation of end-expiratory reading may not always be adequate. A review of physiological and anatomical data, supported by recent imaging, leads to the practical recommendation of zero leveling at the cross-section of three transthoracic planes, which are, respectively midchest frontal, transverse through the fourth intercostal space, and midsagittal. As for the inevitable respiratory pressure swings, end-expiratory reading at functional residual capacity allows for minimal influence of elastic lung recoil on pulmonary pressure reading. However, hyperventilation is associated with changes in end-expiratory lung volume and increased intrathoracic pressure, eventually exacerbated by expiratory muscle contraction and dynamic hyperinflation, all increasing pulmonary vascular pressures. This problem is amplified in patients with obstructed airways. With the exception of dynamic hyperinflation states, it is reasonable to assume that negative inspiratory and positive expiratory intrathoracic pressures cancel each other out, so averaging pulmonary vascular pressures over several respiratory cycles is most often preferable. This recommendation may be generalized for the purpose of consistency and makes sense, as pulmonary blood flow measurements are not corrected for phasic inspiratory and expiratory changes in clinical practice.
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Dobutamine stress echocardiography for the assessment of pressure-flow relationships of the pulmonary circulation.
Chest
PUBLISHED: 03-15-2014
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Stress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mPpa-Q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mPpa-Q relationships.
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Pulmonary vasoreactivity in spontaneously hypertensive rats--effects of endothelin-1 and leptin.
Respir. Res.
PUBLISHED: 01-17-2014
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Systemic hypertension may be associated with an increased pulmonary vascular resistance, which we hypothesized could be, at least in part, mediated by increased leptin.
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Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: clinical associations.
J. Heart Lung Transplant.
PUBLISHED: 01-16-2014
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Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival.
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Key role of the endothelial TGF-?/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.
PLoS ONE
PUBLISHED: 01-01-2014
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Mutations affecting transforming growth factor-beta (TGF-?) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-?/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-?, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-? on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/-) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-? levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-? led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-?/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.
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Maximal cardiac output determines 6 minutes walking distance in pulmonary hypertension.
PLoS ONE
PUBLISHED: 01-01-2014
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The 6 minutes walk test (6MWT) is often shown to be the best predictor of mortality in pulmonary hypertension (PH) probably because it challenges the failing heart to deliver adequate cardiac output. We hypothesised that the 6MWT elicits maximal cardiac output as measured during a maximal cardiopulmonary exercise testing (CPET).
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Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.
J. Am. Coll. Cardiol.
PUBLISHED: 10-15-2013
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Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.
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Physiology of the pulmonary circulation and the right heart.
Curr. Hypertens. Rep.
PUBLISHED: 10-08-2013
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The pulmonary circulation is a high-flow and low-pressure circuit. The functional state of the pulmonary circulation is defined by pulmonary vascular pressure-flow relationships conforming to distensible vessel models with a correction for hematocrit. The product of pulmonary arterial compliance and resistance is constant, but with a slight decrease as a result of increased pulsatile hydraulic load in the presence of increased venous pressure or proximal pulmonary arterial obstruction. An increase in left atrial pressure is transmitted upstream with a ratio ?1 for mean pulmonary artery pressure and ?1 the diastolic pulmonary pressure. Therefore, the diastolic pressure gradient is more appropriate than the transpulmonary pressure gradient to identify pulmonary vascular disease in left heart conditions. Exercise is associated with a decrease in pulmonary vascular resistance and an increase in pulmonary arterial compliance. Right ventricular function is coupled to the pulmonary circulation with an optimal ratio of end-systolic to arterial elastances of 1.5-2.
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Assessment and prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary hypertension.
Circulation
PUBLISHED: 09-20-2013
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This study sought to analyze a new approach to assess exercise-induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure.
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PULMONARY CIRCULATION AND GAS EXCHANGE AT EXERCISE IN SHERPAS AT HIGH ALTITUDE.
J. Appl. Physiol.
PUBLISHED: 07-18-2013
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Tibetans have been reported to present with a unique phenotypic adaptation to high altitude characterized by higher resting ventilation (VE) and arterial oxygen saturation (SpO2), no excessive polycythemia and lower pulmonary artery pressures (Ppa) compared to other high altitude populations. How this affects exercise capacity is not exactly known. We measured aerobic exercise capacity during an incremental cardiopulmonary exercise test (CPET), lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) at rest, and mean Ppa (mPpa) and cardiac output by echocardiography at rest and at exercise in 13 Sherpas and in 13 acclimatized lowlander controls at the altitude of 5050 m in Nepal. In Sherpas versus lowlanders, SpO2 was 86 ± 1 vs 83 ± 2 %, mean ± SE (P NS), mPpa at rest 19 ± 1 vs 23 ± 1 mmHg (P<0.05), DLCO corrected for hemoglobin 61 ± 4 vs 37 ± 2 ml/min/mmHg (P<0.001), DLNO 226 ± 18 vs 153 ± 9 ml/min/mmHg (P<0.001), maximum oxygen uptake (VO2max) 32 ± 3 vs 28 ± 1 ml/kg/min (P NS) and ventilatory equivalent for carbon dioxide at anaerobic threshold 40 ± 2 vs 48 ± 2 (P<0.001). VO2max was correlated directly to DLCO and inversely to the slope of mPpa-cardiac index relationships in both Sherpas and acclimatized lowlanders. We conclude that Sherpas compared to acclimatized lowlanders have an unremarkable aerobic exercise capacity but with less pronounced pulmonary hypertension, lower ventilatory responses and higher lung diffusing capacity.
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Pulmonary hypertension and chronic mountain sickness.
High Alt. Med. Biol.
PUBLISHED: 06-26-2013
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Chronic mountain sickness is a syndrome of severe symptomatic polycythemia and hypoxemia occurring in natives or long-term high altitude sojourners. The condition may be complicated by pulmonary hypertension in proportion to decreased oxygenation, indicating hypoxic vasoconstriction and remodeling. Exercise in these patients is associated with a steep slope of pulmonary artery pressure-flow relationships and decreased vascular distensibility. Correction of pulmonary vascular resistance for increased hematocrit decreases the severity of pulmonary hypertension. Exercise-induced pulmonary hypertension in chronic mountain sickness does not affect exercise capacity, in relation to high oxygen content of the blood and increased lung diffusing capacity. Right ventricular failure seems to be an uncommon complication of chronic mountain sickness, but the exact prevalence of the condition is not known. Acetazolamide given for 6 months to patients with chronic mountain sickness improves oxygenation, polycythemia, and pulmonary artery pressure.
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Downregulated bone morphogenetic protein signaling in nitrofen-induced congenital diaphragmatic hernia.
Pediatr. Surg. Int.
PUBLISHED: 06-24-2013
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Bone morphogenetic proteins (BMP) have been shown to play crucial roles in not only lung and heart development, but also in the pathogenesis of pulmonary vascular remodeling in pulmonary hypertension (PH). We therefore hypothesized that BMP signaling could be altered in nitrofen-induced congenital diaphragmatic hernia (CDH) and associated PH.
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Left ventricular adaptation to acute hypoxia: a speckle-tracking echocardiography study.
J Am Soc Echocardiogr
PUBLISHED: 05-23-2013
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Hypoxia depresses myocardial contractility in vitro but does not affect or may even improve indices of myocardial performance in vivo, possibly through associated changes in autonomic nervous system tone. The aim of this study was to explore the effects of hypoxic breathing on speckle-tracking echocardiographic indices of left ventricular function, with and without ?1-adrenergic inhibition.
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Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 05-17-2013
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This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR × Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n = 78), proximal CTEPH (n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH (n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of ?25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 ± 0.11 s compared with post-PEA-CTEPH (0.37 ± 0.11 s, P < 0.0001), IPAH (0.63 ± 0.14 s, P < 0.001), and distal CTEPH (0.55 ± 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP.
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Pulmonary hypertension and the right ventricle in hypoxia.
Exp. Physiol.
PUBLISHED: 04-26-2013
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Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.
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Lung membrane conductance and capillary volume derived from the NO and CO transfer in high-altitude newcomers.
J. Appl. Physiol.
PUBLISHED: 04-18-2013
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Acute exposure to high altitude may induce changes in carbon monoxide (CO) membrane conductance (DmCO) and capillary lung volume (Vc). Measurements were performed in 25 lowlanders at Brussels (D0), at 4,300 m after a 2- or 3-day exposure (D2,3) without preceding climbing, and 5 days later (D7,8), before and after an exercise test, under a trial with two arterial pulmonary vasodilators or a placebo. The nitric oxide (NO)/CO transfer method was used, assuming both infinite and finite values to the NO blood conductance (?NO). Doppler echocardiography provided hemodynamic data. Compared with sea level, lung diffusing capacity for CO increased by 24% at D2,3 and is returned to control at D7,8. The acute increase in lung diffusing capacity for CO resulted from increases in DmCO and Vc with finite and infinite ?NO assumptions. The alveolar volume increased by 16% at D2,3 and normalized at D7,8. The mean increase in systolic arterial pulmonary pressure at rest at D2,3 was minimal. In conclusion, the acute increase in Vc may be related to the increase in alveolar volume and to the increase in capillary pressure. Compared with the infinite ?NO value, the use of a finite ?NO value led to about a twofold increase in DmCO value and to a persistent increase in DmCO at D7,8 compared with D0. After exercise, DmCO decreased slightly less in subjects treated by the vasodilators, suggesting a beneficial effect on interstitial edema.
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Pulmonary vascular reserve and exercise capacity at sea level and at high altitude.
High Alt. Med. Biol.
PUBLISHED: 03-30-2013
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It has been suggested that increased pulmonary vascular reserve, as defined by reduced pulmonary vascular resistance (PVR) and increased pulmonary transit of agitated contrast measured by echocardiography, might be associated with increased exercise capacity. Thus, at altitude, where PVR is increased because of hypoxic vasoconstriction, a reduced pulmonary vascular reserve could contribute to reduced exercise capacity. Furthermore, a lower PVR could be associated with higher capillary blood volume and an increased lung diffusing capacity. We reviewed echocardiographic estimates of PVR and measurements of lung diffusing capacity for nitric oxide (DL(NO)) and for carbon monoxide (DL(CO)) at rest, and incremental cardiopulmonary exercise tests in 64 healthy subjects at sea level and during 4 different medical expeditions at altitudes around 5000 m. Altitude exposure was associated with a decrease in maximum oxygen uptake (VO2max), from 42±10 to 32±8 mL/min/kg and increases in PVR, ventilatory equivalents for CO2 (V(E)/VCO2), DL(NO), and DL(CO). By univariate linear regression VO2max at sea level and at altitude was associated with V(E)/VCO2 (p<0.001), mean pulmonary artery pressure (mPpa, p<0.05), stroke volume index (SVI, p<0.05), DL(NO) (p<0.02), and DL(CO) (p=0.05). By multivariable analysis, VO2max at sea level and at altitude was associated with V(E)/VCO2, mPpa, SVI, and DL(NO). The multivariable analysis also showed that the altitude-related decrease in VO2max was associated with increased PVR and V(E)/VCO2. These results suggest that pulmonary vascular reserve, defined by a combination of decreased PVR and increased DL(NO), allows for superior aerobic exercise capacity at a lower ventilatory cost, at sea level and at high altitude.
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Proximal pulmonary arterial obstruction decreases the time constant of the pulmonary circulation and increases right ventricular afterload.
J. Appl. Physiol.
PUBLISHED: 03-28-2013
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The time constant of the pulmonary circulation, or product of pulmonary vascular resistance (PVR) and compliance (Ca), called the RC-time, has been reported to remain constant over a wide range of pressures, etiologies of pulmonary hypertension, and treatments. We wondered if increased wave reflection on proximal pulmonary vascular obstruction, like in operable chronic thromboembolic pulmonary hypertension, might also decrease the RC-time and thereby increase pulse pressure and right ventricular afterload. Pulmonary hypertension of variable severity was induced either by proximal obstruction (pulmonary arterial ensnarement) or distal obstruction (microembolism) eight anesthetized dogs. Pulmonary arterial pressures (Ppa) were measured with high-fidelity micromanometer-tipped catheters, and pulmonary flow with transonic technology. Pulmonary ensnarement increased mean Ppa, PVR, and characteristic impedance, decreased Ca and the RC-time (from 0.46 ± 0.07 to 0.30 ± 0.03 s), and increased the oscillatory component of hydraulic load (Wosc/Wtot) from 25 ± 2 to 29 ± 2%. Pulmonary microembolism increased mean Ppa and PVR, with no significant change in Ca and characteristic impedance, increased RC-time from 0.53 ± 0.09 to 0.74 ± 0.05 s, and decreased Wosc/Wtot from 26 ± 2 to 13 ± 2%. Pulse pressure increased more after pulmonary ensnarement than after microembolism. Concomitant measurements with fluid-filled catheters showed the same functional differences between the two types of pulmonary hypertension, with, however, an underestimation of Wosc. We conclude that pulmonary hypertension caused by proximal vs. distal obstruction is associated with a decreased RC-time and increased pulsatile component of right ventricular hydraulic load.
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Physiological response to the 6-minute walk test in chronic heart failure patients versus healthy control subjects.
Eur J Prev Cardiol
PUBLISHED: 03-19-2013
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BACKGROUND: The distance walked in 6 minutes (6MWD) has been reported to be linearly related to peak oxygen uptake (VO2) in cardiac diseases and in lung diseases. In these patients, the VO2 during a 6-min walk test (walkVO2) has been found to be nearly equivalent to peakVO2, but with a lower respiratory exchange ratio (RER). Whether these observations translate to the less functionally impaired patients or healthy control subjects is not exactly known. METHODS: Thirty-two healthy control subjects and 15 chronic heart failure (CHF) patients performed a 6-min walk test and a maximal cardiopulmonary exercise test (CPET) both with measurements of gas exchange. RESULTS: The 6MWD and peakVO2 were linearly correlated, but with an increased slope appearing above 532?m. In CHF patients, walkVO2 was similar to peakVO2, but with lower heart rate and ventilation than measured at peak exercise. In healthy control subjects, VO2, ventilation and heart rate were lower during the 6-min walk than at maximal exercise but higher than at the anaerobic threshold. The RER during the 6-min walk remained <1 in both groups. CONCLUSIONS: Above 500?m, 6MWD becomes less sensitive to any increase in peakVO2. Furthermore, CHF patients and healthy control subjects exercise respectively at maximal and high VO2, but below the anaerobic threshold (as assessed by a CPET) during the 6-min walk test.
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Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension.
Int. J. Cardiol.
PUBLISHED: 03-05-2013
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Echocardiographic studies have contributed to progress in the understanding of the pathophysiology of the pulmonary circulation and have been shown to be useful for screening for and prognostication of pulmonary hypertension, but are considered unreliable for the diagnosis of pulmonary hypertension. We explored this apparent paradox with rigorous Bland and Altman analysis of the accuracy and the precision of measurements collected in a large patient population.
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Chronic thromboembolic pulmonary hypertension: role of medical therapy.
Eur. Respir. J.
PUBLISHED: 02-08-2013
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Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease with poor prognosis if not treated. The treatment of choice is surgery with pulmonary endarterectomy. However, a significant percentage of patients are deemed non-operable due to distal distribution of the disease and arteriopathy in the non-occluded areas that is indistinguishable from pulmonary arterial hypertension (PAH). The overlap in clinical presentation, pathological features and pathogenesis between PAH and CTEPH provides a compelling rationale for exploring the efficacy of PAH-targeted therapies in CTEPH. These therapies are often considered for non-operable patients and are also used in operable patients as a bridge to surgery or as post-pulmonary endarterectomy therapy for persistent pulmonary hypertension, despite the fact they are not licensed for CTEPH. Two randomised clinical trials have been performed in non-operable CTEPH patients. The BENEFiT study, with the endothelin receptor antagonist bosentan, did not show improvement in walking distance. Recently, the CHEST-1 trial, with the soluble guanylate cyclase stimulator riociguat, met study end-point and demonstrated significant improvement in walking distance in patients with non-operable CTEPH. There is an urgent need for more randomised clinical trials designed to clarify whether administration of PAH-targeted therapies improves clinically meaningful end-points in various CTEPH populations.
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Exercise-induced pulmonary hypertension: physiological basis and methodological concerns.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 01-24-2013
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Exercise stresses the pulmonary circulation through increases in cardiac output (.Q) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)-flow relationships ranges from 0.5 to 3 mm Hg.min.L(-1). The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a .Q of less than 10 L.min(-1) or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multipoint PAP-flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase .Q at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology.
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Worsening in oxygen saturation and exercise capacity predict adverse outcome in patients with Eisenmenger syndrome.
Int. J. Cardiol.
PUBLISHED: 01-05-2013
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To evaluate (1) changes in clinical, biochemical and echocardiographic parameters, (2) whether deterioration in exercise capacity and resting oxygen saturation (SatO2-rest) are related with adverse outcome and (3) its additional value in predicting outcome in Eisenmenger patients.
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Stroma cell-derived factor-1? signaling enhances calcium transients and beating frequency in rat neonatal cardiomyocytes.
PLoS ONE
PUBLISHED: 01-03-2013
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Stroma cell-derived factor-1? (SDF-1?) is a cardioprotective chemokine, acting through its G-protein coupled receptor CXCR4. In experimental acute myocardial infarction, administration of SDF-1? induces an early improvement of systolic function which is difficult to explain solely by an anti-apoptotic and angiogenic effect. We wondered whether SDF-1? signaling might have direct effects on calcium transients and beating frequency.Primary rat neonatal cardiomyocytes were culture-expanded and characterized by immunofluorescence staining. Calcium sparks were studied by fluorescence microscopy after calcium loading with the Fluo-4 acetoxymethyl ester sensor. The cardiomyocyte enriched cellular suspension expressed troponin I and CXCR4 but was vimentin negative. Addition of SDF-1? in the medium increased cytoplasmic calcium release. The calcium response was completely abolished by using a neutralizing anti-CXCR4 antibody and partially suppressed and delayed by preincubation with an inositol triphosphate receptor (IP3R) blocker, but not with a ryanodine receptor (RyR) antagonist. Calcium fluxes induced by caffeine, a RyR agonist, were decreased by an IP3R blocker. Treatment with forskolin or SDF-1? increased cardiomyocyte beating frequency and their effects were additive. In vivo, treatment with SDF-1? increased left ventricular dP/dtmax.These results suggest that in rat neonatal cardiomyocytes, the SDF-1?/CXCR4 signaling increases calcium transients in an IP3-gated fashion leading to a positive chronotropic and inotropic effect.
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Heme oxygenase-1 and inflammation in experimental right ventricular failure on prolonged overcirculation-induced pulmonary hypertension.
PLoS ONE
PUBLISHED: 01-01-2013
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Heme oxygenase (HO)-1 is a stress response enzyme which presents with cardiovascular protective and anti-inflammatory properties. Six-month chronic overcirculation-induced pulmonary arterial hypertension (PAH) in piglets has been previously reported as a model of right ventricular (RV) failure related to the RV activation of apoptotic and inflammatory processes. We hypothesized that altered HO-1 signalling could be involved in both pulmonary vascular and RV changes. Fifteen growing piglets were assigned to a sham operation (n = 8) or to an anastomosis of the left innominate artery to the pulmonary arterial trunk (n = 7). Six months later, hemodynamics was evaluated after closure of the shunt. After euthanasia of the animals, pulmonary and myocardial tissue was sampled for pathobiological evaluation. Prolonged shunting was associated with a tendency to decreased pulmonary gene and protein expressions of HO-1, while pulmonary gene expressions of interleukin (IL)-33, IL-19, intercellular adhesion molecule (ICAM)-1 and -2 were increased. Pulmonary expressions of constitutive HO-2 and pro-inflammatory tumor necrosis factor (TNF)-? remained unchanged. Pulmonary vascular resistance (evaluated by pressure/flow plots) was inversely correlated to pulmonary HO-1 protein and IL-19 gene expressions, and correlated to pulmonary ICAM-1 gene expression. Pulmonary arteriolar medial thickness and PVR were inversely correlated to pulmonary IL-19 expression. RV expression of HO-1 was decreased, while RV gene expressions TNF-? and ICAM-2 were increased. There was a correlation between RV ratio of end-systolic to pulmonary arterial elastances and RV HO-1 expression. These results suggest that downregulation of HO-1 is associated to PAH and RV failure.
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Improvement in lung diffusion by endothelin A receptor blockade at high altitude.
J. Appl. Physiol.
PUBLISHED: 10-06-2011
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Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (Vo(2 max)). The diffusing capacities for nitric oxide (DL(NO)) and carbon monoxide (DL(CO)) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DL(CO) (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DL(CO), DL(NO), and Dm but a slight decrease in Vc. Exercise at altitude decreased DL(NO) and Dm. Sitaxsentan intake improved Vo(2 max) together with an increase in resting and postexercise DL(NO) and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DL(NO). Both DL(CO) and DL(NO) were correlated to Vo(2 max) at sea level (r = 0.41-0.42, P < 0.1) and more so at altitude (r = 0.56-0.59, P < 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity.
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Opposing effects of bone morphogenetic protein-2 and endothelin-1 on lung fibroblast chloride currents.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 06-09-2011
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Alteration in the control of bone morphogenetic protein (BMP)-regulated genes and increased expression of endothelin (ET)-1 are both believed to play important roles in the still incompletely understood pathobiology of pulmonary vascular remodeling and fibrosis. Recent studies have drawn attention to the contribution of adventitial fibroblast activation in these phenomena. Because chloride channels are involved in the control of physiological function of fibroblasts, we hypothesized that these channels are differentially regulated by BMPs and ET. We measured chloride ion currents by whole-cell path-clamping in cultured primary human pulmonary fibroblasts. The application of BMP2 prevented activation of these currents by hypotonic challenge in a time- and dose-dependent manner, partially via protein kinase C signaling. Maximal inhibition was observed after 45-minute incubation of cells in the presence of 10 ng/ml of BMP2. ET-1 did not activate chloride channels acutely; however, prolonged treatment of cells with ET-1 (100 nM, 2 h) induced the appearance of lysophosphatidic acid-activated chloride currents (a marker of differentiated myofibroblasts), and this induction could be effectively blocked by BMP2 pretreatment (10 ng/ml). BMP2 also prevented stimulation of ?-smooth muscle actin gene expression and cell migration of fibroblasts induced by ET-1. We conclude that ET-1 and BMP2 have opposing effects on chloride channel activity in human fibroblasts. This is a potentially relevant mechanism involved in pulmonary vascular remodeling and fibrosis.
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Iron deficiency is associated with adverse outcome in Eisenmenger patients.
Eur. Heart J.
PUBLISHED: 05-23-2011
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Iron deficiency is common in patients with Eisenmenger syndrome (ES). This study aimed at evaluating (i) whether iron deficiency is related with adverse outcome, (ii) the determinants of iron deficiency, and (iii) the relation between iron reserves and haemoglobin level in a contemporary cohort of ES patients.
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Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure.
Eur. Heart J.
PUBLISHED: 05-23-2011
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Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension (PAH) model with preserved right ventricular (RV) function. We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure.
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Effects of epoprostenol and sildenafil on right ventricular function in hypoxic volunteers: a tissue Doppler imaging study.
Eur. J. Appl. Physiol.
PUBLISHED: 04-11-2011
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Sildenafil and epoprostenol are effective therapies in pulmonary arterial hypertension (PAH). Both drugs increase cardiac output, which has been in part attributed to improved right ventricular (RV) contractility. We therefore used tissue Doppler imaging (TDI) to test whether sildenafil and epoprostenol might differently affect RV function in normal subjects before and after induction of acute hypoxic pulmonary hypertension. Ten healthy volunteers underwent this randomized, double-blind, placebo-controlled cross-over study. Echocardiographic measurements were obtained 60 min after the intake of a placebo or 50 mg sildenafil or under 8 ng/kg/min iv epoprostenol, in normoxia or after 60 min of hypoxic breathing (FIO(2) of 0.12). Right ventricular systolic function was assessed by systolic strain (?), strain rate (SR), isovolumic contraction acceleration (IVA) and tricuspid annulus plane systolic excursion (TAPSE), and diastolic function by tricuspid annulus E/A ratio and isovolumic relaxation time related to RR interval (IRT/RR). Pulmonary artery pressure was calculated from the acceleration time of pulmonary flow and cardiac output from the left ventricular outflow tract flow-velocity. Hypoxia increased pulmonary vascular resistance (PVR) by 78%, did not affect indices of RV systolic function, decreased E/A and increased IRT/RR. Epoprostenol more than sildenafil increased cardiac output, apical ? and TAPSE, the latter in proportion to decreased PVR. In addition, apical SR was increased only by epoprostenol. None of the drugs affected IVA, basal SR, E/A and IRT/RR. These results are not suggestive of intrinsic positive inotropic effects of either sildenafil or epoprostenol at maximal doses tolerated by normal subjects.
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Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials.
J. Heart Lung Transplant.
PUBLISHED: 03-02-2011
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Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil.
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Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension.
Br J Clin Pharmacol
PUBLISHED: 01-12-2011
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To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily.
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[The cardiopulmonary exercise test in the management of patients with pulmonary hypertension].
Arch. Bronconeumol.
PUBLISHED: 01-01-2011
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The main symptom of patients with pulmonary hypertension (PH) is exercise intolerance. The gold standard for evaluation of exercise capacity is the incremental cardio-pulmonary exercise test (ICPET) on a bicycle ergometer. Exercise tolerance in patients with PH is mainly determined by the capacity to increase cardiac output to meet metabolic demands, which depends on right ventricular function. Therefore, right ventricular dysfunction is the main factor limiting exercise tolerance in PH. Patients with PH also show hypoxemia during exercise and hyperventilation is also common, both at rest and during exercise, which can be attributed to greater chemosensitivity. The present review analyzes the physiological mechanisms determining exercise tolerance, exercise response in patients with PH, the variables of greatest interest in the study of this disorder, the similarities and differences between ICPET and other, simpler tests such as the 6-minute walk test, and the prognostic value of exercise testing in these patients. Evaluation of exercise tolerance is an essential element in the clinical assessment of patients with PH. Consequently, detailed knowledge of the information provided by exercise testing and its limitation is of undoubted interest in the clinical management of this complex disease.
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Range in pulmonary artery systolic pressure among highly trained athletes.
Chest
PUBLISHED: 09-23-2010
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Although the physiologic range of pulmonary artery systolic pressure (PASP) has been reported, data on how it is manifested in athletes are limited. The aim of the present study was to explore the full spectrum of PASP and the long-term training impact in a large population of highly trained athletes.
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Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 08-06-2010
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Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.
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Early right ventriculo-arterial uncoupling in borderline pulmonary hypertension on experimental heart failure.
J. Appl. Physiol.
PUBLISHED: 08-05-2010
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Pulmonary hypertension on heart failure (HF) limits exercise capacity and survival probably because of associated right ventricular (RV) failure. This study investigated the mechanisms of RV function adaptation to early pulmonary hypertension in experimental HF. Seven weeks of rapid ventricular pacing in six dogs induced a HF characterized by cardiomegaly and decreased left ventricular ejection fraction. Compared with eight control dogs, pulmonary hypertension was borderline, with a mean pulmonary artery pressure increased to only 23 ± 2 (means ± SE) mmHg. However, the pulmonary vascular impedance spectrum was globally shifted to higher pressures, with an increase in 0 Hz impedance (resistance) to 662 ± 69 vs. 455 ± 41 dynes·cm(-5)·m(2) in controls (P < 0.01) and in characteristic impedance to 183 ± 20 vs. 104 ± 7 dynes·cm(-5)·m(2) in controls (P < 0.01). There was no change in RV end-systolic elastance (Ees), but arterial elastance (Ea) was increased to 1.8 ± 0.3 vs. 0.9 ± 0.1 mmHg/ml in controls so that RV-arterial coupling defined by the Ees-to-Ea ratio (Ees/Ea) was decreased to 0.8 ± 0.1 vs. 1.5 ± 0.1 in controls (P < 0.01). Inhaled nitric oxide, 40 ppm or 5 ?g·kg(-1)·min(-1) nitroprusside i.v., did not affect Ees/Ea. Fifty milligrams (i.v.) of milrinone increased Ees/Ea to 1.6 ± 0.2 by an isolated increase in Ees. We conclude that overpacing-induced HF is accompanied by a borderline pulmonary hypertension but profound RV-arterial uncoupling explained by the failure of RV systolic function to adapt combined effects of increased pulmonary arterial resistance and elastance.
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Right ventricular load at exercise is a cause of persistent exercise limitation in patients with normal resting pulmonary vascular resistance after pulmonary endarterectomy.
Chest
PUBLISHED: 07-29-2010
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Pulmonary endarterectomy (PEA) provides a potential cure for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, successfully operated patients can continue to suffer from a limitation of exercise capacity, despite normalization of pulmonary vascular resistance (PVR). The purpose of the present study was to explore the cardiopulmonary exercise test (CPET) profile and the pulmonary hemodynamic response to exercise in these patients.
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Pulmonary vasoreactivity predicts long-term outcome in patients with Eisenmenger syndrome receiving bosentan therapy.
Heart
PUBLISHED: 07-28-2010
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Vasoreactivity testing is recommended in the management of pulmonary arterial hypertension (PAH), but its clinical relevance in congenital heart disease (CHD)-associated PAH has not been established.
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Pulmonary capillary blood volume and membrane conductance in Andeans and lowlanders at high altitude: A cross-sectional study.
Nitric Oxide
PUBLISHED: 05-21-2010
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Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.
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Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure.
Crit. Care Med.
PUBLISHED: 05-01-2010
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The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways.
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Physiological adaptation of the cardiovascular system to high altitude.
Prog Cardiovasc Dis
PUBLISHED: 04-27-2010
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Altitude exposure is associated with major changes in cardiovascular function. The initial cardiovascular response to altitude is characterized by an increase in cardiac output with tachycardia, no change in stroke volume, whereas blood pressure may temporarily be slightly increased. After a few days of acclimatization, cardiac output returns to normal, but heart rate remains increased, so that stroke volume is decreased. Pulmonary artery pressure increases without change in pulmonary artery wedge pressure. This pattern is essentially unchanged with prolonged or lifelong altitude sojourns. Ventricular function is maintained, with initially increased, then preserved or slightly depressed indices of systolic function, and an altered diastolic filling pattern. Filling pressures of the heart remain unchanged. Exercise in acute as well as in chronic high-altitude exposure is associated with a brisk increase in pulmonary artery pressure. The relationships between workload, cardiac output, and oxygen uptake are preserved in all circumstances, but there is a decrease in maximal oxygen consumption, which is accompanied by a decrease in maximal cardiac output. The decrease in maximal cardiac output is minimal in acute hypoxia but becomes more pronounced with acclimatization. This is not explained by hypovolemia, acid-bases status, increased viscosity on polycythemia, autonomic nervous system changes, or depressed systolic function. Maximal oxygen uptake at high altitudes has been modeled to be determined by the matching of convective and diffusional oxygen transport systems at a lower maximal cardiac output. However, there has been recent suggestion that 10% to 25% of the loss in aerobic exercise capacity at high altitudes can be restored by specific pulmonary vasodilating interventions. Whether this is explained by an improved maximum flow output by an unloaded right ventricle remains to be confirmed. Altitude exposure carries no identified risk of myocardial ischemia in healthy subjects but has to be considered as a potential stress in patients with previous cardiovascular conditions.
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New therapies for pulmonary arterial hypertension: an update on current bench to bedside translation.
Expert Opin Investig Drugs
PUBLISHED: 04-07-2010
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Treatments of pulmonary arterial hypertension (PAH) that have so far proven efficacious are all based on the restoration of endothelium control of pulmonary vascular tone and structure, by administration of prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. However, results remain unsatisfactory, with persistent high mortality, insufficient clinical improvement and no convincing report of any reversal of the disease process.
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Ventricular-arterial uncoupling in heart failure with preserved ejection fraction after myocardial infarction in dogs - invasive versus echocardiographic evaluation.
BMC Cardiovasc Disord
PUBLISHED: 03-03-2010
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Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs.
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Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 03-01-2010
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The sympathetic nervous system has been reported to be activated in pulmonary arterial hypertension (PAH). Objectives: We investigated the prognostic significance of muscle sympathetic nervous system activity (MSNA) in PAH.
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Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.
Br. J. Haematol.
PUBLISHED: 02-17-2010
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Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0.006) with non-significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0.07) and between 6MWD and right atrial pressure (P = 0.08). In ASSET-2 at baseline, there was a non-significant correlation between 6MWD and CO (P = 0.06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non-significant increases in CO were observed with bosentan compared to placebo. Similarly, non-significant decreases in PVR were observed with bosentan. Limited data in SCD-PH suggest that a low 6MWD predicts a low CO. Standard-dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.
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Impedance in isolated mouse lungs for the determination of site of action of vasoactive agents and disease.
Ann Biomed Eng
PUBLISHED: 02-03-2010
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Hypoxic pulmonary hypertension is a disease of the lung vasculature that is usually quantified by pulmonary vascular resistance (PVR). However, a more complete description of lung vascular function and right ventricular afterload is provided by pulmonary vascular impedance (PVZ) from spectral analysis of pulsatile pressure-flow relationships. We studied pulsatile pressure-flow relationships in isolated, perfused lungs of mice in normoxia, after induction of hypoxic pulmonary hypertension by 10 days of hypoxic exposure, and after the administration of the vasoactive agents sodium nitroprusside and serotonin in order to gain insight into the effects of disease and vasoactive agents on afterload. Chronic hypoxia exposure increased 0 Hz impedance (Z(0)) from 2.0 +/- 0.2 to 3.3 +/- 0.2 mmHg min/mL but decreased characteristic impedance (Z(C)) from 0.21 +/- 0.02 to 0.18 +/- 0.01 mmHg min/mL (both p < 0.05). Sodium nitroprusside only slightly decreased Z(0) but increased Z(C) in normal lungs (p < 0.05) and did not affect Z(C) and decreased Z(0) in hypertensive lungs (p < 0.05). Serotonin increased Z(C) in normal and hypertensive lungs but decreased Z(0) in hypertensive lungs (p < 0.05). There was an inverse correlation between mean pulmonary artery pressure and Z(C) in all circumstances. These findings demonstrate that vasoactive interventions can have different sites of action (i.e., proximal vs. distal segments) in the normal and chronically hypoxic pulmonary vasculature, and the pressure-dependency of Z(C) and R(W). The measurement of PVZ in isolated lungs allows for an improved understanding of the modes of action of drugs and hypoxia on the pulmonary circulation.
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Changes in plasma bradykinin concentration and citric acid cough threshold at high altitude.
Wilderness Environ Med
PUBLISHED: 12-25-2009
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Altitude-related cough is a troublesome condition of unknown etiology. Inhaled tussive agents are used to quantify cough, and the citric acid cough threshold has been shown to fall on ascent to altitude. Cough can occur in patients taking angiotensin-converting enzyme inhibitors due to stimulation of airway sensory receptors by increased levels of bradykinin. We hypothesized that increased levels of bradykinin could be responsible for the decrease in citric acid cough threshold on exposure to altitude and a possible etiologic factor in altitude-related cough.
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How to measure pulmonary vascular and right ventricular function.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 12-08-2009
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Long-standing pulmonary hypertension causes significant peripheral and proximal arterial remodeling and right ventricular dysfunction. The clinical metric most often used to assess the progression of PH is the pulmonary vascular resistance (PVR). However, even when measured from multipoint pressure-flow curves, PVR provides information only on the peripheral arterial function, not the proximal arterial function and gives only an incomplete description of all the forces that oppose right ventricular (RV) flow output. Pulmonary vascular impedance spectra (PVZ) capture the impact of proximal and peripheral arterial structure and function on RV function. Analyses of ventricular-vascular coupling give insight into the efficiency of mechanical and metabolic interactions between the right ventricle and the pulmonary vasculature. Here we review techniques for measuring PVZ in humans and animal models and for determining RV function.
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How to measure peripheral pulmonary vascular mechanics.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 12-08-2009
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Pulmonary hypertension (PH) is initially a disease of the small, peripheral resistance arteries. Changes in these vessels are best assessed by measurement of pulmonary artery pressure at several levels of flow to generate multi-point pressure-flow curves. This approach is superior to the traditional single-point measurement of pulmonary vascular resistance (PVR) because it allows a flow-independent definition of the resistive properties of that portion of the pulmonary vascular bed and also provides information on its distensibility. In animal models, multi-point pressure-flow curves can be obtained using an isolated, ventilated, perfused lung system. Clinically, cardiopulmonary exercise testing (CPET) with non-invasive echocardiography is feasible and provides realistic values of the resistance and peripheral compliance. Together, these values can be used to better understand and screen for PH and exercise-induced PH.
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The Belgian Eisenmenger syndrome registry: implications for treatment strategies?
Acta Cardiol
PUBLISHED: 09-04-2009
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Pulmonary arterial hypertension (PAH), associated with congenital heart disease (CHD), usually results from a systemic-to-pulmonary shunt. Eisenmenger syndrome (ES) is characterised by severe irreversible PAH and reversal of a previous systemic-to-pulmonary shunt. A national registry of ES patients was initiated to optimise patient care and to provide epidemiological information regarding PAH and CHD in Belgium.
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Serotonin decreases alveolar epithelial fluid transport via a direct inhibition of the epithelial sodium channel.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 08-28-2009
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Hypoxia and epithelial stretch that are commonly observed in patients with acute lung injury have been shown to promote the release of serotonin (5-hydroxytryptamine, 5-HT) in vitro. However, whether 5-HT contributes to the decrease of alveolar epithelial fluid transport, which is a hallmark of lung injury, is unknown. Thus, we investigated the effect of 5-HT on ion and fluid transport across the alveolar epithelium. 5-HT caused a dose-dependent inhibition of the amiloride-sensitive current across primary rat and human alveolar epithelial type II cell monolayers, but did not affect Na(+)/K(+) ATPase function. Furthermore, we found that the 5-HT induced inhibition of ion transport across the lung epithelium was receptor independent, as it was not prevented by the blockade of 5-HT2R (5-HT receptor 2), 5-HT3R (5-HT receptor 3), or by pretreatment with an intracellular calcium-chelating agent, BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N,N-tetraacetic acid tetra(acetoxymethyl) ester). In addition, the stimulation of 5-HT1R (5-HT receptor 1), 5-HT2R (5-HT receptor 2), 5-HT4R (5-HT receptor 4), and 5-HT7R (5-HT receptor 7) failed to reproduce the 5-HT effect on amiloride-sensitive sodium transport. We ascertained that 5-HT directly inhibited the function of rat alphabetagamma epithelial sodium channel (ENaC), as determined by heterologous expression of rat ENaC in Xenopus oocytes that do not express endogenous ENaC nor 5-HT receptors (5-HTR). Exposure of mice to hypoxia for 1 hour induced a 30% increase of 5-HT secretion into the distal airways of mice. Finally, the intratracheal instillation of 5-HT inhibited the amiloride-sensitive fraction of alveolar fluid clearance in mice. Together, these results indicate that 5-HT inhibits the amiloride-sensitive fraction of the alveolar epithelial fluid transport via a direct interaction with ENaC, and thus can be an endogenous inhibitor of this ion channel.
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Effects of digoxin on muscle reflexes in normal humans.
Eur. J. Appl. Physiol.
PUBLISHED: 08-06-2009
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Blockade of the skeletal muscle Na(+)-K(+)-ATPase pump by digoxin could result in a more marked hyperkaliema during a forearm exercise, which in turn could stimulate the mechano- and metaboreceptors. In a randomized, double-blinded, placebo-controlled, and cross-over-design study, we measured mean blood pressure (MBP), heart rate (HR), ventilation (V(E)), oxygen saturation (SpO(2)), muscle sympathetic nerve activity (MSNA), venous plasma potassium and lactic acid during dynamic handgrip exercises, and local circulatory arrest in 11 healthy subjects. Digoxin enhanced MBP during exercise but not during the post-handgrip ischemia and had no effect on HR, V(E), SpO(2), and MSNA. Venous plasma potassium and lactic acid were also not affected by digoxin-induced skeletal muscle Na(+)-K(+)-ATPase blockade. We conclude that digoxin increased MBP during dynamic exercise in healthy humans, independently of changes in potassium and lactic acid. A modest direct sensitization of the muscle mechanoreceptors is unlikely and other mechanisms, independent of muscle reflexes and related to the inotropic effects of digoxin, might be implicated.
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Expression of vasoactive intestinal peptide and related receptors in overcirculation-induced pulmonary hypertension in piglets.
Pediatr. Res.
PUBLISHED: 07-08-2009
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The pathobiology of pulmonary arterial hypertension (PAH) is not understood completely. Recent observations in patients with PAH and in knockout models have raised the idea that a defect in vasoactive intestinal peptide (VIP) may be involved in PAH physiopathology. Therefore, we investigated the expressions of VIP, the related pituitary adenylate cyclase-activating polypeptide (PACAP), and their receptors (VPAC1, VPAC2, and PAC1) in piglets with overcirculation-induced pulmonary hypertension as an early-stage PAH model. Seventeen piglets were randomized to an anastomosis between the innominate and the main pulmonary artery, or to a sham operation. After 3 mo, a hemodynamic evaluation was performed and the lung tissue was sampled for biologic and histologic studies. The shunting increased pulmonary vascular resistance (PVR) by 100% and arteriolar medial thickness by 85%. VIP and VPAC1 gene expressions were decreased and increased, respectively. VPAC1 gene expression was positively correlated to PVR. VPAC2 and PAC1 immunoreactivity was seen in pulmonary arterial smooth muscle. VIP and PACAP immunostaining was observed in nerve fibers surrounding the pulmonary arterial smooth muscle. In conclusion, overcirculation-induced pulmonary hypertension is accompanied by a down-regulation of VIP signaling, without change in PACAP expression. These results are consistent with the notion that abnormal VIP signaling takes part in PAH pathogenesis.
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Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy.
BMC Cardiovasc Disord
PUBLISHED: 07-03-2009
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Insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGFbeta) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy.
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Aerobic exercise capacity in COPD patients with and without pulmonary hypertension.
Respir Med
PUBLISHED: 04-04-2009
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Pulmonary hypertension is a common occurrence in advanced COPD, but its effects on exercise capacity remain undetermined. Exercise testing and an echocardiographic examination were performed in 29 patients with advanced stable COPD. Mean pulmonary artery pressure (mPAP) was calculated from the acceleration time of pulmonary flow. Exercise capacity was evaluated by the distance walked in 6 min (6MWD) and by an incremental cardiopulmonary exercise test (CPET). The patients had a forced expiratory volume in 1s of 1.13+/-0.49 L, and a 6MWD of 305+/-66 m (mean+/-SD). The CPET (n=24) showed a: maximum workload of 52+/-25 W, a peak O(2) uptake of 13.8+/-4.4 mL/kg/min, a peak heart rate of 127+/-22 bpm, a peak respiratory exchange ratio 1.06+/-0.11, a ventilation (V(E))/CO(2) production slope of 37+/-11, and a peak O(2) pulse 7.5+/-2.3 mL. The peak V(E) was 41+/-15 L/min, and the calculated maximum voluntary V(E) 45+/-20 L/min. There was no difference in any of the CPET variables and 6MWD between the patients with a mPAP<30 mm Hg (mPAP 22+/-6 mm Hg, n=15) and those with a mPAP>30 mm Hg (mPAP 38+/-6 mm Hg, n=14). There was no correlation between PAP and any of the exercise measurements. These results suggest that exercise capacity in unselected patients with advanced COPD and mild to moderate pulmonary hypertension is essentially limited by exhaustion of the ventilatory reserve.
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Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia.
Circulation
PUBLISHED: 03-23-2009
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This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene.
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The effect of posture-induced changes in peripheral nitric oxide uptake on exhaled nitric oxide.
J. Appl. Physiol.
PUBLISHED: 03-19-2009
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Airway and alveolar NO contributions to exhaled NO are being extracted from exhaled NO measurements performed at different flow rates. To test the robustness of this method and the validity of the underlying model, we deliberately induced a change in NO uptake in the peripheral lung compartment by changing body posture between supine and prone. In 10 normal subjects, we measured exhaled NO at target flows ranging from 50 to 350 ml/s in supine and prone postures. Using two common methods, bronchial NO production [Jaw(NO)] and alveolar NO concentration (FANO) were extracted from exhaled NO concentration vs. flow or flow(-1) curves. There was no significant Jaw(NO) difference between prone and supine but a significant FANO decrease from prone to supine ranging from 23 to 33% depending on the method used. Total lung capacity was 7% smaller supine than prone (P = 0.03). Besides this purely volumetric effect, which would tend to increase FANO from prone to supine, the observed degree of FANO decrease from prone to supine suggests a greater opposing effect that could be explained by the increased lung capillary blood volume (V(c)) supine vs. prone (P = 0.002) observed in another set of 11 normal subjects. Taken together with the relative changes of NO and CO transfer factors, this V(c) change can be attributed mainly to pulmonary capillary recruitment from prone to supine. Realistic models for exhaled NO simulation should include the possibility that a portion of the pulmonary capillary bed is unavailable for NO uptake, with a maximum capacity of the pulmonary capillary bed in the supine posture.
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Cell therapy with autologous bone marrow mononuclear stem cells is associated with superior cardiac recovery compared with use of nonmodified mesenchymal stem cells in a canine model of chronic myocardial infarction.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 02-13-2009
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Stem cell therapy can facilitate cardiac repair in infarcted myocardium, but the optimal cell type remains uncertain. We conducted a randomized, blind, and placebo-controlled comparison of autologous bone marrow mononuclear cell and mesenchymal stem cell therapy in a large-animal model of chronic myocardial infarction.
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Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.
J. Am. Coll. Cardiol.
PUBLISHED: 02-06-2009
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The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term "non-PAH PH" summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.
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Diagnosis and assessment of pulmonary arterial hypertension.
J. Am. Coll. Cardiol.
PUBLISHED: 02-06-2009
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The diagnosis and assessment of pulmonary arterial hypertension is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging and follow-up assessment. The definition of pulmonary hypertension has been simplified, and is now based on currently available evidence. There has been substantial progress in advancing the imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. The importance of accurate assessment of right ventricular function in following up the clinical course and response to therapy is more fully appreciated. As new therapies are developed for pulmonary arterial hypertension, screening, prompt diagnosis, and accurate assessment of disease severity become increasingly important. A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from our expanding therapeutic armamentarium.
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Bosentan decreases pulmonary vascular resistance and improves exercise capacity in acute hypoxia.
Chest
PUBLISHED: 02-02-2009
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Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic healthy subjects.
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Improvement in right ventricular function during reversibility testing in pulmonary arterial hypertension: a case report.
Cardiovasc Ultrasound
PUBLISHED: 01-26-2009
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A right heart catheterization with reversibility testing is recommended for the diagnosis and treatment of pulmonary arterial hypertension. In this 24 years-old woman, the inhalation of 5 microg iloprost transiently decreased mean pulmonary artery pressure from 62 to 36 mmHg and pulmonary vascular resistance from 11.0 to 4.9 Wood units, meeting the criteria of a "positive response". The echocardiographic examination showed normalization of right heart chamber dimensions and of the right ventricular performance (Tei) index. Pulsed tissue Doppler imaging of the right ventricle showed a decrease in the isovolumic relaxation time from 102 to 73 ms, and an increase of the E/A ratio from 0.72 to 1.38, together with marked improvements in mid-apical free wall systolic strain and strain rate. A positive response to reversibility testing of pulmonary arterial hypertension may be associated with quasi normalization of right ventricular function, in spite of still elevated pulmonary artery pressure.
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Acute pulmonary embolism: relationships between ground-glass opacification at thin-section CT and hemodynamics in pigs.
Radiology
PUBLISHED: 01-21-2009
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To investigate the link between acute pulmonary embolism (PE) and occurrence of ground-glass opacity (GGO) and the relationships between this occurrence and hemodynamics in an animal model of acute PE.
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Echocardiographic and tissue Doppler imaging of cardiac adaptation to high altitude in native highlanders versus acclimatized lowlanders.
Am. J. Cardiol.
PUBLISHED: 01-04-2009
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High-altitude exposure is a cause of pulmonary hypertension and decreased exercise capacity, but associated changes in cardiac function remain incompletely understood. The aim of this study was to investigate right ventricular (RV) and left ventricular function in acclimatized Caucasian lowlanders compared with native Bolivian highlanders at high altitudes. Standard echocardiography and tissue Doppler imaging studies were performed in 15 healthy lowlanders at sea level; <24 hours after arrival in La Paz, Bolivia, at 3,750 m; and after 10 days of acclimatization and ascent to Huayna Potosi, at 4,850 m, and the results were compared with those obtained in 15 age- and body size-matched inhabitants of Oruro, Bolivia, at 4,000 m. Acute exposure to high altitude in lowlanders caused an increase in mean pulmonary arterial pressure, to 20 to 25 mm Hg, and altered RV and left ventricular diastolic function, with prolonged isovolumic relaxation time, an increased RV Tei index, and maintained RV systolic function as estimated by tricuspid annular plane excursion and the tricuspid annular S wave. This profile was essentially unchanged after acclimatization and ascent to 4,850 m, except for higher pulmonary arterial pressure. The native highlanders presented with relatively lower pulmonary arterial pressures but more pronounced alterations in diastolic function, decreased tricuspid annular plane excursion and tricuspid annular S waves, and increased RV Tei indexes. In conclusion, cardiac adaptation to high altitude was qualitatively similar in acclimatized Caucasian lowlanders and in Bolivian native highlanders. However, lifelong exposure to high altitude may be associated with different cardiac adaptation to milder hypoxic pulmonary hypertension.
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