Echocardiographic right ventricular strain from multiple apical views is superior for assessment of right ventricular systolic function.

BACKGROUND: Right ventricular (RV) systolic function is an important determinant of outcome in patients with pulmonary hypertension (PH). Conventional echocardiographic measures of RV are mainly based on longitudinal contractility. Recently, measurement of RV global longitudinal strain derived from multiple windows (RVGLS) has emerged as an option but has not been well evaluated. The aim of the present study was to evaluate which echocardiographic RV function parameter correlates best with RV ejection fraction derived from cardiac magnetic resonance imaging (RVEFCMR ). METHODS AND RESULTS: Fifty-five patients evaluated for PH underwent RV assessment with echocardiography and CMR. Conventional echocardiographic parameters of RV function including tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (S'), RV fractional area change (RVFAC) and RV index of myocardial performance (RIMP). RVGLS was measured from three separate apical views using a 17-segment model and strain from the lateral free wall was calculated separately (RVfree). The study included 55 patients, whereas assessment of RVGLS could be obtained in 29 patients. The Pearson correlation coefficient with RVEFCMR was strong for RVGLS (r = 0·814, P<0·001) and RVfree (r = 0·778, P<0·001), modest for RVFAC (r = 0·681, P<0·001), TAPSE (r = 0·592, P<0·001) and RIMP (r=-0·521, P<0·01), and weak for S' (r = 0·385, P<0·01). CONCLUSION: The echocardiographic RV measures, RVGLS and RVfree correlated well with RVEFCMR , whereas correlation with TAPSE, RIMP and S' was unsatisfactory. Our findings suggest that RVGLS and RVfree are the preferred echocardiographic methods for clinical practice. RVfree is easiest to perform but RVGLS could provide incremental value in selected patients.

Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension.

OBJECTIVE: To identify circulating angiogenic and inflammatory biomarkers with potential in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc), and in early diagnosis and determination of treatment response in PAH. METHOD: Plasma samples were taken at the time of PAH diagnosis and at treatment follow-up after a median (interquartile range) of 4 months (3-9.8 months) in idiopathic (n = 9) and SSc-associated PAH (n = 11). In patients with SSc-associated PAH, plasma samples had also been gathered a median of 2 years (0.8-3 years) before PAH diagnosis (n = 10). Additional plasma samples were retrieved at two time-points separated by a median of 12 years (10-13 years) from SSc patients who did not develop PAH (n = 10) and from controls (n = 8). Angiogenic and inflammatory biomarkers were analysed by multiplex immunoassays. RESULTS: Plasma levels of placenta growth factor (PlGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and tumour necrosis factor-α (TNF-α) were higher (p < 0.05) in SSc patients who later developed PAH than in those who did not. Plasma vascular endothelial growth factor (VEGF)-D increased (p < 0.05) in SSc patients as PAH developed. Plasma levels of PlGF, VEGF-A, VEGF-D, sVEGFR-1, interleukin-6, and TNF-α were higher (p < 0.05) in PAH than controls. There were no significant differences in circulating biomarkers between idiopathic and SSc-associated PAH. Plasma sVEGFR-1 decreased (p < 0.05) after initiating PAH-targeted treatments. CONCLUSIONS: Plasma levels of PlGF, sVEGFR-1, TNF-α, and VEGF-D have potential in screening for SSc-associated PAH. Plasma sVEGFR-1 may be a biomarker of treatment response.

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension.

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation-perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right-heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin-1 and thromboxane A2 may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase-1 in acute hypoxia, but to cyclooxygenase-2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5-hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.

Regional contribution to ventricular stroke volume is affected on the left side, but not on the right in patients with pulmonary hypertension.

To develop more sensitive measures of impaired cardiac function in patients with pulmonary hypertension (PH), since detection of impaired right ventricular (RV) function is important in these patients. With the hypothesis that a change in septal function in patients with PH is associated with altered longitudinal and lateral function of both ventricles, as a compensatory mechanism, we quantified the contributions of these parameters to stroke volume (SV) in both ventricles using cardiac magnetic resonance (CMR). Seventeen patients (10 females) evaluated for PH underwent right heart catheterization (RHC) and CMR. CMR from 33 healthy adults (13 females) were used as controls. Left ventricular (LV) atrioventricular plane displacement (AVPD) and corresponding longitudinal contribution to LVSV was lower in patients (10.8 ± 3.2 mm and 51 ± 12 %) compared to controls (16.6 ± 1.9 mm and 59 ± 9 %, p < 0.0001 and p < 0.01, respectively). This decrease did not differ in patient with ejection fraction (EF) >50 % and <50 % (p = 0.5) and was compensated for by increased LV lateral contribution to LVSV in patients (49 ± 13 % vs. 37 ± 7 %, p = 0.001). Septal motion contributed less to LVSV in patients (5 ± 8 %) compared to controls (8 ± 4 %, p = 0.05). RV AVPD was lower in patients (12.0 ± 3.6 mm vs. 21.8 ± 2.2 mm, p < 0.0001) but longitudinal and lateral contribution to RVSV did not differ between patients (78 ± 17 % and 29 ± 16 %) and controls (79 ± 9 % and 31 ± 6 % p = 0.7 for both) explained by increased RV cross sectional area in patients. LV function is affected in patients with PH despite preserved global LV function. The decreased longitudinal contribution and increased lateral contribution to LVSV was not seen in the RV, contrary to previous findings in patients with volume loaded RVs.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

A new equation to estimate temperature-corrected PaCO2 from PET CO2 during exercise in normoxia and hypoxia.

End-tidal PCO2 (PET CO2 ) has been used to estimate arterial pressure CO2 (Pa CO2 ). However, the influence of blood temperature on the Pa CO2 has not been taken into account. Moreover, there is no equation validated to predict Pa CO2 during exercise in severe acute hypoxia. To develop a new equation to predict temperature-corrected Pa CO2 values during exercise in normoxia and severe acute hypoxia, 11 volunteers (21.2 ± 2.1 years) performed incremental exercise to exhaustion in normoxia (Nox, PI O2 : 143 mmHg) and hypoxia (Hyp, PI O2 : 73 mmHg), while arterial blood gases and temperature (ABT) were simultaneously measured together with end-tidal PCO2 (PET CO2 ). The Jones et al. equation tended to underestimate the temperature corrected (tc) Pa CO2 during exercise in hypoxia, with greater deviation the lower the Pa CO2 tc (r = 0.39, P < 0.05). The new equation has been developed using a random-effects regression analysis model, which allows predicting Pa CO2 tc both in normoxia and hypoxia: Pa CO2 tc = 8.607 + 0.716 × PET CO2 [R(2) = 0.91; intercept SE = 1.022 (P < 0.001) and slope SE = 0.027 (P < 0.001)]. This equation may prove useful in noninvasive studies of brain hemodynamics, where an accurate estimation of Pa CO2 is needed to calculate the end-tidal-to-arterial PCO2 difference, which can be used as an index of pulmonary gas exchange efficiency.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial.

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3­6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7­11 weeks and everolimus exposure increased (6­10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7­11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Pathophysiology and potential treatments of pulmonary hypertension due to systolic left heart failure.

Pulmonary hypertension (PH) due to left heart failure is becoming increasingly prevalent and is associated with poor outcome. The precise pathophysiological mechanisms behind PH due to left heart failure are, however, still unclear. In its early course, PH is caused by increased left ventricular filling pressures, without pulmonary vessel abnormalities. Conventional treatment for heart failure may partly reverse such passive PH by optimizing left ventricular function. However, if increased pulmonary pressures persist, endothelial damage, excessive vasoconstriction and structural changes in the pulmonary vasculature may occur. There is, at present, no recommended medical treatment for this active component of PH due to left heart failure. However, as the vascular changes in PH due to left heart failure may be similar to those in pulmonary arterial hypertension (PAH), a selected group of these patients may benefit from PAH treatment targeting the endothelin, nitric oxide or prostacyclin pathways. Such potent pulmonary vasodilators could, however, be detrimental in patients with left heart failure without pulmonary vascular pathology, as selective pulmonary vasodilatation may lead to further congestion in the pulmonary circuit, resulting in pulmonary oedema. The use of PAH therapies is therefore currently not recommended and would require the selection of suitable patients based on the underlying causes of the disease and careful monitoring of their progress. The present review focuses on the following: (i) the pathophysiology behind PH resulting from systolic left heart failure, and (ii) the current evidence for medical treatment of this condition, especially the role of PAH-targeted therapies in systolic left heart failure.

sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.

AIM: Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan. METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2)~0.21) and hypoxia (FiO(2)~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 µg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 µg min(-1) per kg (protocol 3, n = 6). RESULTS: Hypoxia (n = 18) increased (P < 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P < 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions. CONCLUSION: BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.

Cyclooxygenase-2 inhibition and thromboxane A(2) receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model.

AIM: Hypoxic pulmonary vasoconstriction (HPV) causes pulmonary hypertension that may lead to right heart failure. We hypothesized that the COX-2 inhibitor nimesulide and the thromboxane A(2) receptor antagonist daltroban would attenuate HPV. METHODS: Haemodynamic measurements and blood sampling were performed in 18 anaesthetized, mechanically ventilated pigs, with mean ± SEM weights of 31.3 ± 0.6 kg, in normoxia (F(i)O(2)~0.21) and hypoxia (F(i)O(2)~0.10), before and 5, 15 and 45 min after initiation of right atrial infusion of nimesulide (n = 6) or daltroban (n = 6), respectively, and in six control pigs. RESULTS: Compared with normoxia, hypoxia (n = 18) increased mean pulmonary artery pressure by 15.8 ± 0.8 mmHg (P < 0.001), pulmonary vascular resistance (PVR) by 2.7 ± 0.3 WU (P < 0.05) and mean right atrial pressure by 2.3 ± 0.3 mmHg (P < 0.001). In the control pigs, mean pulmonary artery pressure, PVR and mean right atrial pressure remained stable (P = ns) throughout 45 min hypoxia, compared with hypoxia baseline. Nimesulide decreased mean pulmonary artery pressure by 3.7 ± 1.3 mmHg after 45 min (P < 0.013), as well as PVR by 0.8 ± 0.2 WU (P < 0.05), levelling off after 15 min. Daltroban transiently increased (P < 0.001) mean pulmonary artery pressure and mean right atrial pressure by 7.2 ± 1.2 and 2.7 ± 0.4 mmHg, respectively, but they returned to hypoxia baseline (P = ns) within 5 min. Daltroban then decreased mean pulmonary artery pressure to after 45 min be 4.2 ± 1.6 mmHg lower (P < 0.005) than at hypoxia baseline. CONCLUSION: COX-2 inhibition and thromboxane A(2) receptor antagonism attenuate HPV by decreasing mean pulmonary artery pressure by approximately 10-11%, as measured 45 min after initiation of nimesulide or daltroban infusion respectively.

Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia-induced pulmonary vasoconstriction in a porcine model.

AIM: Our aim was to test the hypothesis that dual endothelin receptor blockade with tezosentan attenuates hypoxia-induced pulmonary vasoconstriction. METHODS: Fourteen anaesthetized, ventilated pigs, with a mean ± SEM weight of 30.5 ± 0.6 kg, were studied, in normoxia (FiO(2) 0.21) and with tezosentan (5 mg kg(-1)) infusion during (n = 7) or before (n = 7) hypoxia (FiO(2) 0.10). RESULTS: Compared to normoxia, hypoxia increased (P < 0.05) pulmonary vascular resistance (PVR) by 3.4 ± 0.7 WU, mean pulmonary artery pressure by 13.7 ± 1.3 mmHg, mean right atrial pressure by 1.9 ± 0.4 mmHg and decreased (P < 0.02) systemic vascular resistance (SVR) by 5.2 ± 2.1 WU. Pulmonary capillary wedge pressure (PCWP), mean aortic blood pressure, heart rate, cardiac output, stroke volume and blood-O(2)-consumption were unaltered (P = ns). Tezosentan infused during hypoxia, normalized PVR, decreased (P < 0.05) maximally mean pulmonary artery pressure by 7.5 ± 0.8 mmHg, SVR by 5.8 ± 0.7 WU, mean aortic blood pressure by 10.8 ± 3.0 mmHg and increased (P < 0.04) stroke volume by 8.5 ± 1.8 mL. Mean right atrial pressure, PCWP, heart rate, cardiac output and blood-O(2) -consumption were unaltered (P = ns). Tezosentan infused before hypoxia additionally attenuated approx. 70% of the initial mean pulmonary artery pressure increase and abolished the PVR increase, without additionally affecting the other parameters. CONCLUSION: Dual endothelin receptor blockade during hypoxia attenuates the 'sustained' acute pulmonary vasoconstrictor response by reducing the mean pulmonary artery pressure increase by approx. 62% and by normalizing PVR. Pre-treatment with tezosentan before hypoxia, additionally attenuates the initial hypoxia-induced mean pulmonary artery pressure rise by approx. 70% and abolishes the PVR increase, during stable circulatory conditions, without affecting oxygenation.

Exercise limb blood flow response to acute and chronic hypoxia in Danish lowlanders and Aymara natives.

AIM: The femoral artery blood flow response to submaximal, one-legged, dynamic, knee-extensor exercise was determined in acute and chronic hypoxia to investigate the hypotheses that with adaptation to chronic hypoxia blood haemoglobin increases, allowing preservation of blood flow as in normoxia. METHODS: Sixteen Danish lowlanders participated, in groups of six to eight, in the experiments at sea level normoxia (FiO2 congruent with 0.21) and acute hypoxia (FiO2 congruent with 0.11), and chronic hypoxia after approximately 7 and 9-10 weeks at approximately 5260 m altitude breathing ambient air (FiO2 congruent with 0.21) or a hyperoxic gas (FiO2 congruent with 0.55). The response was compared with that in six Aymara natives. RESULTS: The haemoglobin and haematocrit increased (P < 0.003) in the lowlanders at altitude vs. at sea level by approximately 39 and 27% respectively; i.e. to a similar (P = ns) level as in the natives. At rest, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. During the onset of and incremental exercise, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. Acute hypoxia increased (P < 0.05) blood flow by approximately 55% during exercise in the lowlanders at sea level. Acute hyperoxia decreased (P < 0.05) blood flow by approximately 22-29% during exercise in the lowlanders and natives at altitude. CONCLUSION: In chronic hypoxia, blood haemoglobin increases, allowing normalization of the elevated exercise blood flow response in acute hypoxia, and preservation of the kinetics and steady-state exercise blood flow as in normoxia, being similar as in the natives at altitude.

Differences in exercising limb blood flow variability between cardiac and muscle contraction cycle related analysis during dynamic knee extensor.

AIM: Blood flow in peripheral conduit arteries during steady-state, dynamic exercise, can be estimated noninvasively with Doppler ultrasound, by measuring the conduit arterial diameter and the mean blood velocity averaged over consecutive cardiac beat-by-beat cycles (BB(cycle)) or muscle contraction-relaxation cycles (CR(cycle)). The precise impact fluctuations in the 1-BB(cycle)- or 1-CR(cycle)-rate may impose on the average blood flow measurements has previously not been clearly defined. The hypothesis investigated in the present study was that the blood flow measurements obtained, and its variability, during exercise, may differ between the 1-BB(cycle) and 1-CR(cycle) at incremental exercise intensities; as the BB(cycle)-measurements may be influenced by transient alterations in heart rate; whereas the CR(cycle)-measurements are dependent on the muscle contraction-relaxation frequencies independent of the exercise intensities per se. The main purpose was therefore to determine if fluctuations in blood flow for 1-BB(cycle) and 1-CR(cycle)varies at incremental exercise intensities (work rates) using the one-legged dynamic knee-extensor exercise (DKE) model. METHODS: Limb femoral artery blood flow (LBF) was determined, for 1-BB(cycle) and 1-CR(cycle), in 8 healthy male subjects during 4-min of steady-state DKE at 60 contractions per minute at 10, 20, 30 and 40 W. The variability of LBF was determined from the coefficients of variation (CVLBF). RESULTS: The CV(LBF) for the CR(cycle)-measurements at each work rate were similar (P=NS). The CV(LBF) for the BB(cycle)-measurements were higher (P<0.05) at 40 W compared to at 10 W. Furthermore, the CV(LBF) for the 1-BB(cycle) was higher (P<0.05) than for the 1-CR(cycle) at 30 and 40 W, despite almost identical mean LBF values for the BB(cycle)- and the CR(cycle)-measurements at each exercise intensity. CONCLUSIONS: The present data suggests that estimates of LBF at slightly higher exercise intensities such as above 30 W, for a few number of consecutive BB(cycle), renders a higher variability than for CR(cycle)-measurements. This may consequently result in slight over- and under-estimations of LBF compared to the CR(cycle)-measurement.

Determinants of maximal oxygen uptake in severe acute hypoxia.

To unravel the mechanisms by which maximal oxygen uptake (VO2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, approximately 5,300 m above sea level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P < 0.001). Forty-one percent of the reduction in CaO2 was explained by the lower inspired O2 pressure (PiO2) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O2 difference in hypoxia (P < 0.05). Hypoxia caused a 47% decrease in VO2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% (P < 0.01), due to equal reductions in both peak heart rate and stroke VOlume (P < 0.05). Peak leg blood flow was also lower (by 22%, P < 0.01). Consequently, systemic and leg O2 delivery were reduced by 43 and 47%, respectively, with hypoxia (P < 0.001) correlating closely with VO2 max (r = 0.98, P < 0.001). Therefore, three main mechanisms account for the reduction of VO2 max in severe acute hypoxia: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in VO2 max.

Why is VO2 max after altitude acclimatization still reduced despite normalization of arterial O2 content?

Acute hypoxia (AH) reduces maximal O2 consumption (VO2 max), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O2 saturation that can normalize arterial O2 concentration ([O2]), VO2 max remains low. To determine why, seven lowlanders were studied at VO2 max (cycle ergometry) at sea level (SL), after 9-10 wk at 5,260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (FiO2 = 0.105) equivalent to 5,260 m. Pulmonary and leg indexes of O2 transport were measured in each condition. Both cardiac output and leg blood flow were reduced by approximately 15% in both AH and CH (P < 0.05). At maximal exercise, arterial [O2] in AH was 31% lower than at SL (P < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O2 extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76% of the cardiac output perfused the legs, in CH the legs received only 67%. Pulmonary VO2 max (4.1 +/- 0.3 l/min at SL) fell to 2.2 +/- 0.1 l/min in AH (P < 0.05) and was only 2.4 +/- 0.2 l/min in CH (P < 0.05). These data suggest that the failure to recover VO2 max after acclimatization despite normalization of arterial [O2] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.

Effect of blood haemoglobin concentration on V(O2,max) and cardiovascular function in lowlanders acclimatised to 5260 m.

The principal aim of this investigation was to determine the influence of blood haemoglobin concentration ([Hb]) on maximal exercise capacity and maximal O(2) consumption (V(O(2),max)) in healthy subjects acclimatised to high altitude. Secondarily, we examined the effects of [Hb] on the regulation of cardiac output (CO), blood pressure and muscular blood flow (LBF) during exercise. Eight Danish lowlanders (three females and five males; 24 +/- 0.6 years, mean +/- S.E.M.) performed submaximal and maximal exercise on a cycle ergometer after 9 weeks at an altitude of 5260 m (Mt Chacaltaya, Bolivia). This was done first with the high [Hb] resulting from acclimatisation and again 2-4 days later, 1 h after isovolaemic haemodilution with Dextran 70 to near sea level [Hb]. After measurements at maximal exercise while breathing air at each [Hb], subjects were switched to hyperoxia (55 % O(2) in N(2)) and the measurements were repeated, increasing the work rate as tolerated. Hyperoxia increased maximal power output and leg V(O(2),max), showing that breathing ambient air at 5260 m, V(O(2),max) is limited by the availability of O(2) rather than by muscular oxidative capacity. Altitude increased [Hb] by 36 % from 136 +/- 5 to 185 +/- 5 g l(-1) (P < 0.001), while haemodilution (replacing 1 l of blood with 1 l of 6 % Dextran) lowered [Hb] by 24 % to 142 +/- 6 g l(-1) (P < 0.001). Haemodilution had no effect on maximal pulmonary or leg V(O(2),max), or power output. Despite higher LBF, leg O(2) delivery was reduced and maximal V(O(2)) was thus maintained by higher O(2) extraction. While CO increased linearly with work rate irrespective of [Hb] or inspired oxygen fraction (F(I,O(2))), both LBF and leg vascular conductance were systematically higher when [Hb] was low. Close and significant relationships were seen between LBF (and CO) and both plasma noradrenaline and K(+) concentrations, independently of [Hb] and F(I,O(2)). In summary, under conditions where O(2) supply limits maximal exercise, the increase in [Hb] with altitude acclimatisation does not improve maximal exercise capacity or V(O(2),max), and does not alter peak CO. However, LBF and vascular conductance are higher at altitude when [Hb] is lowered to sea level values, with both relating closely to catecholamine and potassium concentrations. This suggests that the lack of effect of [Hb] on V(O(2),max) may involve reciprocal changes in LBF via local metabolic control of the muscle vasculature.

Human skeletal muscle fatty acid and glycerol metabolism during rest, exercise and recovery.

UNLABELLED: This study was conducted to investigate skeletal muscle fatty acid (FA) and glycerol kinetics and to determine the contribution of skeletal muscle to whole body FA and glycerol turnover during rest, 2 h of one-leg knee-extensor exercise at 65 % of maximal leg power output, and 3 h of recovery. To this aim, the leg femoral arterial-venous difference technique was used in combination with a continuous infusion of [U-(13)C]palmitate and [(2)H(5)]glycerol in five post-absorptive healthy volunteers (22 +/- 3 years). The influence of contamination from non-skeletal muscle tissues, skin and subcutaneous adipose tissue, on FA and glycerol kinetics was studied by catheterization of the femoral vein in antegrade and retrograde directions. Substantially higher net leg FA and glycerol uptakes were observed with a retrograde compared to an antegrade catheter position, as a result of a much lower tracer-calculated leg FA and glycerol release. The whole body FA rate of appearance (R(a)) increased with exercise and decreased rapidly in recovery but stayed higher compared to pre-exercise. The leg net FA uptake decreased immediately on cessation of exercise to near pre-exercise level, but the tracer FA uptake and release decreased slowly and reached constant values after approximately 1.5 h of recovery similar to pre-exercise. Whole body FA reesterification (FA R(d) - FA oxidation; R(d), rate of disappearance) was approximately 400 micromol min(-1) at rest and during exercise, and increased during recovery to 495 micromol min(-1). Leg FA reesterification was 17 micromol min(-1) at rest and decreased to 9 micromol min(-1) during recovery, due to a larger fraction of leg FA uptake being directed to oxidation. A net glycerol exchange across the leg could not be detected under all conditions, but a substantial leg glycerol uptake was observed, which was substantially higher during exercise. Total body skeletal muscle FA and glycerol uptake/release was estimated to account for 18-25 % of whole body R(d) or R(a). IN CONCLUSION: (1) skeletal muscle FA and glycerol metabolism, using the leg arterial-venous difference method, can only be studied if contamination from skin and subcutaneous adipose tissue is prevented; (2) whole body FA reesterification is unchanged when going from rest to exercise, but is increased during recovery; (3) in post-absorptive man total body skeletal muscle contributes 17-24 % to whole body FA and glycerol turnover and FA reesterification at rest; (4) glycerol is taken up by skeletal muscle and the uptake increases many fold during exercise.

Whole body and leg acetate kinetics at rest, during exercise and recovery in humans.

We have used a constant [1,2-(13)C]acetate infusion (0.12 micromol x min(-1) x kg( 1)) for 2 h at rest, followed by 2 h of one-legged knee-extensor exercise at 65% of leg maximal workload, and 3 h of recovery in six post-absorptive volunteers to quantify whole-body and leg acetate kinetics and determine whether the whole-body acetate correction factor can be used to correct leg substrate oxidation. The acetate whole-body rate of appearance (R(a)) was not significantly different at rest, during exercise or during recovery (365-415 micromol x min(-1)). The leg net acetate uptake was similar at rest and during recovery (approximately 10 micromol x min(-1)), but increased approximately 5-fold with exercise. At rest the leg acetate uptake (approximately 15 micromol x min(-1)) and release (approximately 5 micromol x min(-1)) accounted for 4 and 1.5 % of whole-body acetate disposal (R(d)) and R(a), respectively. When the leg acetate kinetics were extrapolated to the total body skeletal muscle mass, then skeletal muscle accounted for approximately 16 and approximately 6% of acetate R(d) and R(a). With exercise, leg acetate uptake increased approximately 6-fold, whereas leg acetate release increased 9-fold compared with rest. Whole-body acetate carbon recovery increased with time of infusion at rest and during recovery from 21% after 1.5 h of infusion to 45% in recovery after 7 h of infusion. Leg and whole-body acetate carbon recovery were similar under resting conditions, both before and after exercise. During exercise whole-body acetate carbon recovery was approximately 75%, however, acetate carbon recovery of the active leg was substantially higher (approximately 100%). It is concluded that inactive skeletal muscle plays a minor role in acetate turnover. However, active skeletal muscle enhances several-fold acetate uptake and subsequent oxidation, as well as release and its contribution to whole-body acetate turnover. Furthermore, under resting conditions the whole-body acetate correction factor can be used to correct for leg, skeletal muscle, substrate oxidation, but not during exercise.

Parasympathetic neural activity accounts for the lowering of exercise heart rate at high altitude.

BACKGROUND: In chronic hypoxia, both heart rate (HR) and cardiac output (Q) are reduced during exercise. The role of parasympathetic neural activity in lowering HR is unresolved, and its influence on Q and oxygen transport at high altitude has never been studied. METHODS AND RESULTS: HR, Q, oxygen uptake, mean arterial pressure, and leg blood flow were determined at rest and during cycle exercise with and without vagal blockade with glycopyrrolate in 7 healthy lowlanders after 9 weeks' residence at >/=5260 m (ALT). At ALT, glycopyrrolate increased resting HR by 80 bpm (73+/-4 to 153+/-4 bpm) compared with 53 bpm (61+/-3 to 114+/-6 bpm) at sea level (SL). During exercise at ALT, glycopyrrolate increased HR by approximately 40 bpm both at submaximal (127+/-4 to 170+/-3 bpm; 118 W) and maximal (141+/-6 to 180+/-2 bpm) exercise, whereas at SL, the increase was only by 16 bpm (137+/-6 to 153+/-4 bpm) at 118 W, with no effect at maximal exercise (181+/-2 bpm). Despite restoration of maximal HR to SL values, glycopyrrolate had no influence on Q, which was reduced at ALT. Breathing FIO(2)=0.55 at peak exercise restored Q and power output to SL values. CONCLUSIONS: Enhanced parasympathetic neural activity accounts for the lowering of HR during exercise at ALT without influencing Q. The abrupt restoration of peak exercise Q in chronic hypoxia to maximal SL values when arterial PO(2) and SO(2) are similarly increased suggests hypoxia-mediated attenuation of Q.