Impact of right ventricular reserve on exercise capacity and survival in patients with pulmonary hypertension.

AIMS: Pulmonary hypertension is a clinical syndrome characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are key subgroups of this disorder with comparable clinical and pathological findings. Resting pulmonary haemodynamics correlate only moderately with functional parameters and do not predict prognosis in these patients sufficiently accurately. We therefore correlated exercise haemodynamics with peak oxygen uptake (peakVO2) and determined their prognostic significance. METHODS AND RESULTS: Thirty-six consecutive patients (21 female, 54 ± 15 years) with PAH (n = 21) or inoperable CTEPH were studied. The mean follow-up period was 1709 ± 837 days. All patients underwent right heart catheterization at rest and during exercise, and cardiopulmonary exercise testing. Patients had severe pulmonary hypertension at rest (mean pulmonary artery pressure 46 + 11 mmHg, cardiac index 2.2 ± 0.6 L/min/m(2), pulmonary vascular resistance 861 ± 330 dynes/s/cm(5)). Exercise cardiac index correlated with peakVO2 (r = 0.59, P < 0.001) and was the only independent predictor of peakVO2 on multivariate stepwise linear regression analyses (P < 0.001). PeakVO2 was the strongest predictor of survival (χ(2) = 14.5, P = 0.003). Among haemodynamic variables, only exercise cardiac index (χ(2) = 5.6, P = 0.018) and the slope of the pressure/flow relationship (χ(2) = 4.1, P = 0.04) were significant prognostic indicators. CONCLUSION: The ability of the right ventricle to increase the cardiac index during exercise is an important determinant of exercise capacity in patients with pulmonary hypertension. It also predicts prognosis and might therefore be useful in the clinical assessment of these patients.

Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease despite recent treatment advances. Individual risk stratification is important. Exercise capacity and invasive haemodynamic data are both relevant, but data on the combined prognostic power are lacking. METHODS: 226 consecutive patients with idiopathic or familial PAH were included at seven specialised tertiary centres. All patients underwent right heart catheterization and cardiopulmonary exercise testing (CPET). RESULTS: During follow-up (1508 ± 1070 days) 72 patients died and 30 underwent transplantation. On multivariate analysis percentage of predicted peak oxygen uptake (%predicted peak VO2 [risk ratio 0.95]), pulmonary vascular resistance (PVR [1.105,]) and increase in heart rate during exercise (ΔHR [0.974]) were independent prognostic predictors (all p<0.0001). Peak VO2 allowed for risk stratification with a survival of 100, 92.9, 87.4 and 69.6% at 1 year and 97.7, 63.2, 41 and 23% at 5 years for the 4th, 3rd, 2nd and 1st quartiles, respectively. Dichotomizing by median peak VO2 and intra-group median PVR showed a worse 1-year survival for patients with low peak VO2/higher PVR compared to patients with low peak VO2/low PVR, high peak VO2/high PVR and high peak VO2/low PVR (65 vs. 93, 93, 100%, p<0.001). At 10 years survival was different for all 4 subgroups (19 vs. 25 vs. 48 vs. 75%, adjusted p<0.05). CONCLUSIONS: Peak VO2, PVR and ΔHR independently predict prognosis in patients with PAH. Low peak VO2, high PVR and low ΔHR refer to poor prognosis. Combined use of peak VO2 and PVR provides accurate risk stratification underlining the complementary prognostic information from cardiopulmonary exercise testing and resting invasive haemodynamic data.

Improvement of exercise capacity in monocrotaline-induced pulmonary hypertension by the phosphodiesterase-5 inhibitor Vardenafil.

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension. Four weeks after monocrotaline-administration rats exhibited a significant increase in right ventricular pressure (RVSP, 94mmHg vs. 25mmHg; p=0.001) right ventricular weight (right ventricle/left ventricle+septum, 59 vs. 23; p=0.001) and pulmonary vascular remodeling (medial wall area 104% vs. 66%; p<0.05) as compared to controls, with a corresponding reduction in exercise capacity (% from baseline value: 67%; p<0.05). Vardenafil treatment resulted in decreased RVSP (56mmHg vs. 95mmHg; p=0.008), right ventricular weight (41 vs. 59; p=0.013), pulmonary vascular remodeling (medial wall area 64% vs. 104%; p<0.05) and a significant better exercise capacity (% from baseline value: 84% vs. 67%; p<0.05) compared to monocrotaline only treated animals. In conclusion, Vardenafil exerts beneficial effects on monocrotaline-induced pulmonary hypertension in rats. Whether it is a treatment option for patients with pulmonary hypertension needs to be elucidated.

Pulmonary hypertension: Hemodynamic evaluation. Updated Recommendations of the Cologne Consensus Conference 2011.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the invasive hemodynamic evaluation of pulmonary hypertension. This manuscript describes in detail the results and recommendations of the working group which were last updated in October 2011.

Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan.

RATIONALE: There is evidence that endothelin plays a key role in the development of pulmonary hypertension (PH) in pulmonary fibrosis (PF). However, the functional consequence of the unselective endothelin receptor antagonist Bosentan in PH and PF has not yet been studied. Therefore, we investigated the effects of Bosentan on the development of PH in the model of Bleomycin-induced PF in rats. METHODS: Adult male Wistar rats were randomly assigned to the following groups: untreated animals (controls), Bleomycin-induced PF (Bleomycin) and Bleomycin-induced PF treated with Bosentan (Bleomycin+Bosentan). Exercise capacity was evaluated by treadmill exercise testing. PH was assessed by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. For quantification of PF the hydroxyproline content in lung tissue (HPC) was measured. RESULTS: Compared to controls, animals with Bleomycin-induced PF showed a significant reduction in exercise capacity (44% vs. 100%), significantly higher RVSP (65 mmHg vs. 23 mmHg), significantly more right ventricular hypertrophy (0.55 vs. 0.24) and significantly higher HPC (60.5 vs. 14.8). Bosentan treatment in animals with Bleomycin-induced PF resulted in significantly greater exercise capacity (98% vs. 44%) and a trend towards lower RVSP (52 mmHg vs. 65 mmHg), significantly less right ventricular hypertrophy (0.34 vs. 0.55) and significantly lower HPC (16.7 vs. 60.5) compared to untreated Bleomycin-induced PF. CONCLUSION: Application of Bosentan in Bleomycin rats resulted in significantly higher exercise capacity as a result of improvements in PH and PF.

Effects of dynamic bilevel positive airway pressure support on central sleep apnea in men with heart failure.

BACKGROUND: Treatment with continuous positive airway pressure (CPAP) improves cardiac function in chronic heart failure (CHF) patients with central sleep apnea (CSA)-Cheyne-Stokes respiration (CSR) by stabilizing ventilation, but frequently central apneas and hypopneas persist. Our objective was to test the hypothesis that flow-targeted dynamic bilevel positive airway pressure (BPAP) support (BiPAP autoSV; Respironics; Murrysville, PA) effectively suppresses CSR-CSA in CHF patients. METHODS: We studied 14 CHF patients with CSR-CSA (and residual CSA on positive airway pressure therapy) during 3 consecutive nights: (1) diagnostic polysomnography, (2) CPAP (n=10) or BPAP (n=4) titration, and (3) dynamic flow-targeted dynamic BPAP support with an expiratory positive airway pressure (EPAP) set to suppress obstructive respiratory events, and an inspiratory positive airway pressure (IPAP) dynamically ranging between 0 and 15 cm H2O above the EPAP. RESULTS: CPAP or BPAP significantly reduced the apnea-hypopnea index (AHI) [mean+/-SD, 46+/-4 events/h to 22+/-4 events/h; p=0.001] compared to the first night without treatment. Flow-targeted dynamic BPAP support (mean EPAP, 6.5+/-1.7 cm H2O; maximal IPAP, 21.9+/-2.1 cm H2O) further reduced the AHI to 4+/-1/h of sleep compared to the untreated (p<0.001) and CPAP or BPAP night (p=0.002). After the first night of flow-targeted dynamic BPAP support, patients rated on an analog scale (range, 0 to 10) the treatment as comfortable (6.9+/-0.6), and the sleep quality as improved compared to previous nights (7.4+/-0.6). CONCLUSION: Flow-targeted dynamic BPAP support effectively suppresses CSR-CSA in patients with CHF and is well tolerated.

Nocturnal continuous positive airway pressure improves ventilatory efficiency during exercise in patients with chronic heart failure.

OBJECTIVES: Chronic heart failure is closely related to impaired cardiorespiratory reflex control, including decreased ventilatory efficiency during exercise (Ve/Vco(2)-slope) and central sleep apnea (CSA). Continuous positive airway pressure (CPAP) and nocturnal oxygen therapy alleviate CSA. The aim of the present study was to compare the effects of nocturnal CPAP and oxygen therapy on Ve/Vco(2)-slope. DESIGN AND SETTING: Prospective controlled trial at a university hospital. PATIENTS: Twenty-six stable patients with chronic heart failure and CSA. INTERVENTION AND MEASUREMENTS: Ten patients received nocturnal oxygen, and 16 patients were assigned to CPAP treatment. At baseline and after 12 weeks of treatment, symptom-limited cardiopulmonary exercise testing was performed on a cycle ergometer. Expiratory gas was analyzed breath by breath for evaluation of ventilation and ventilatory efficiency in combination with arteriocapillary blood gas analysis during rest and exercise. RESULTS: CPAP treatment significantly reduced the Ve/Vco(2)-slope (31.2 +/- 1.6 vs 26.2 +/- 1.0, p = 0.005) and improved the left ventricular ejection fraction (LVEF) [31.7 +/- 2.6% vs 35.7 +/- 2.7%, p = 0.041]. CPAP treatment significantly reduced the apnea-hypopnea index (AHI) [35.9 +/- 4.0/h vs 12.2 +/- 3.6/h, p = 0.002]. Peak oxygen consumption (Vo(2)) [16.2 +/- 1.1 L/min/kg vs 16.3 +/- 1.2 L/min/kg, p = 0.755] remained similar after CPAP treatment. Oxygen therapy reduced the AHI (28.8 +/- 3.2/h vs 8.7 +/- 4.1/h, p = 0.019), but did not improve exercise capacity (peak Vo(2), 15.4 +/- 1.5 L/min/kg vs 15.6 +/- 1.9 L/min/kg, p = 0.760), LVEF (30.9 +/- 2.4% vs 32.5 +/- 2.3%, p = 0.231), or the Ve/Vco(2)-slope (30.0 +/- 1.5 vs 29.8 +/- 1.5, p = 0.646). CONCLUSION: Nocturnal CPAP and oxygen therapy alleviate CSA to a similar degree. Only CPAP therapy may improve ventilatory efficiency during exercise and may have favorable effects on LVEF. Therefore, our data suggest that CPAP is advantageous compared to oxygen in the treatment of CSA in patients with chronic heart failure.

Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea.

BACKGROUND: In patients with chronic heart failure (CHF), central sleep apnea (CSA) and enhanced ventilatory response (VE/VCO2 slope) to exercise are common. Both breathing disorders alone indicate poor prognosis in CHF. Although augmented chemosensitivity to CO2 is thought to be one important underlying mechanism for both breathing disorders, it is unclear whether both breathing disorders are related closely in patients with CHF. METHODS AND RESULTS: We investigated 20 CHF patients with clinically important CSA (apnea-hypopnea-index (AHI), number of episodes per hour >or=15) and 10 CHF patients without CSA. Patients with and without CSA did not differ with respect to exercise capacity (peak VO2, 63.4+/-3.4% versus 60.8+/-4.4% of predicted value; P=0.746) and left ventricular ejection fraction (LVEF, 31+/-2% versus 31+/-3%; P=0.948). The AHI was not correlated with exercise capacity (peak VO2, percent of predicted value; P=0.260) and LVEF (percent, P=0.886). In contrast, the positive correlation of the VE/VCO2 slope, determined by cardiopulmonary exercise testing, with the AHI was highly significant (P<0.001). The VE/VCO2 slope was significantly increased in patients with CSA compared with those without CSA (29.7 versus 24.9; P<0.001). CONCLUSIONS: The ventilatory response to exercise is significantly augmented in CHF patients with CSA compared with those without. In contrast to peak VO2 and LVEF, the VE/VCO2 slope is strongly related to the severity of CSA in patients with CHF, which underscores an augmented chemosensitivity to CO2 as a common underlying pathophysiological mechanism.

Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs.

We tested the hypothesis that pulmonary endothelial nitric oxide synthase (eNOS) gene expression is primarily regulated by hemodynamic factors and is thus increased in rats with chronic hypoxic pulmonary hypertension. Furthermore, we examined the role of endothelin (ET)-1 in this regulatory process, since ET-1 is able to induce eNOS via activation of the ET-B receptor. Therefore, chronic hypoxic rats (10% O(2)) were treated with the selective ET-A receptor antagonist LU-135252 (50 mg x kg(-1) x day(-1)). Right ventricular systolic pressure and cross-sectional medial vascular wall area of pulmonary arteries rose significantly, and eNOS mRNA levels increased 1.8- and 2.6-fold after 2 and 4 wk of hypoxia, respectively (each P < 0.05). Pulmonary ET-1 mRNA and ET-1 plasma levels increased significantly after 4 wk of hypoxia (each P < 0.05). LU-135252 reduced right ventricular systolic pressure, vascular remodeling, and eNOS gene expression in chronic hypoxic rats (each P < 0.05), whereas ET-1 production was not altered. We conclude that eNOS expression in chronic hypoxic rat lungs is modified predominantly by hemodynamic factors, whereas the ET-B receptor-mediated pathway and hypoxia seem to be less important.

Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension.

OBJECTIVE: The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension. METHODS: To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day). RESULTS: Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia). CONCLUSION: Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.

Hemodynamic effects of aerosolized iloprost in pulmonary hypertension at rest and during exercise.

STUDY OBJECTIVES: Aerosolized iloprost, a stable prostacyclin analog, improves functional capacity even in patients with pulmonary hypertension who did not show a vigorous hemodynamic response after iloprost inhalation at rest. We therefore speculated that aerosolized iloprost elicits more beneficial effects on pulmonary hemodynamics during exercise than at rest. DESIGN AND SETTING: A prospective, open, uncontrolled study at a university hospital. PATIENTS: Sixteen patients with primary or secondary pulmonary hypertension. INTERVENTIONS: Right-heart catheterization at rest and during exercise before and after the inhalation iloprost, 14 to 28 microg. RESULTS: Before iloprost treatment, exercise increased mean (+/- SD) pulmonary artery pressure (PAPm) from 45 +/- 8 to 70 +/- 13 mm Hg, cardiac output from 3.7 +/- 1.0 to 5.8 +/- 2.4 L/min, and pulmonary vascular resistance (PVR) from 904 +/- 322 to 1,013 +/- 432 dyne.s.cm(-5) (each p < 0.05). After recovery, iloprost reduced PAPm from 44 +/- 8 to 41 +/- 6 mm Hg, increased cardiac output from 3.7 +/- 1.0 to 4.9 +/- 1.4 L/min, and lowered PVR from 902 +/- 350 to 636 +/- 248 dyne x s x cm(-5) (each p < 0.05). During exercise after iloprost, PAPm increased to 57 +/- 8 mm Hg, cardiac output to 7.0 +/- 3.0 L/min, and PVR to 673 +/- 279 dyne x s x cm(-5) (each p < 0.05 vs first exercise test). Systemic BP was not altered significantly by iloprost treatment during exercise. CONCLUSIONS: Aerosolized iloprost treatment exerts more favorable effects on pulmonary hemodynamics during exercise than at rest. These findings explain the functional improvement observed in patients with pulmonary hypertension who show only a moderate pulmonary vasodilatory response during iloprost inhalation at rest. Whether these beneficial effects have prognostic significance needs to be elucidated by further study.