Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin-treated rats.

AIM: Pulmonary fibrosis is often complicated by pulmonary hypertension. Statins reduce fibroblast activity in vitro and pulmonary hypertension in vivo. We investigated whether Simvastatin exerts beneficial effects on pulmonary fibrosis and pulmonary hypertension in Bleomycin-treated rats in vivo. METHODS: Rats were randomly assigned to controls, Bleomycin, Bleomycin plus Simvastatin from day 1 to 28 and Bleomycin plus Simvastatin from day 13 to 28. 28 days after Bleomycin instillation, right ventricular systolic pressure (RVSP), right ventricular mass (RV/(LV+S)), right ventricular and circulating brain natriuretic peptide (BNP) levels were determined to assess pulmonary hypertension. Pulmonary hydroxyproline content (HPC), pulmonary connective tissue growth factor (CTGF) transcription and lung compliance (LC) were analysed to characterize pulmonary fibrosis. Exercise capacity was determined by treadmill tests. RESULTS: Compared with controls, Bleomycin increased RVSP, RV/(LV+S), BNP levels, HPC and CTGF transcription and decreased LC significantly. Simvastatin administered from day 1 to 28 normalized all these parameters. Simvastatin administered from day 13 to 28 had no effect on HPC and LC, but reduced RV/(LV+S) significantly and induced a strong trend to lower RVSP and BNP levels. Exercise capacity was reduced by Bleomycin. Simvastatin significantly improved exercise intolerance in both treatment groups. CONCLUSIONS: Simvastatin prevents the development of pulmonary fibrosis, but fails to attenuate already established pulmonary fibrosis. In contrast, it ameliorates pulmonary hypertension and thereby exercise capacity in the prevention and the treatment group regardless of its effects on pulmonary fibrosis. Whether statins are a treatment option in humans with pulmonary fibrosis needs to be investigated by further study.

Polysomnography underestimates altered cardiac autonomic control in patients with obstructive sleep apnea.

BACKGROUND: Repetitive nocturnal sympathetic activation during episodes of apnea and postapneic hyperventilation increases cardiovascular risk. The effects of hypopnea and non-apneic, non-hypopneic intervals before and after hypopnea/apnea on sympathico-vagal balance have not been assessed yet. HYPOTHESIS: Hypopnea and non-apneic, non-hypopneic intervals before and after hypopnea/apnea cause increased sympathetic activity when compared to normal respiration in nonREM stages 2­4. METHODS: A total of 34 patients were studied using in-laboratory polysomnography including continuous ECG recording. Absolute spectral power of heart rate variability in the very low (VLF), low (LF), and high frequency (HF) bands and low frequency to high frequency power ratio (LF/HF ratio) were analyzed during apnea, hypopnea, and during the pre- and post-phases of such respiratory episodes and compared to spectral powers during normal respiration in nonREM sleep 2­4. RESULTS: Patients with hypopnea and/or obstructive apnea showed higher power of VLF and the LF/HF ratio in intervals of hypopnea/apnea and in non-apneic, non-hypopneic intervals before and after hypopnea/apnea compared to normal respiration in nonREM stages 2­4. CONCLUSION: The effect of sleep-disordered breathing on alteration of autonomic tone in patients with hypopnea and obstructive apnea is more severe than estimated by conventional polysomnographic assessment of apnea and hypopnea. Patients with sleep apnea show a sympathetic overdrive not only during phases of hypopnea and obstructive apnea but also in non-apnea, non-hypopnea intervals before and after hypopnea, and obstructive apnea.

Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) results in chronic right heart failure, which is associated with an increase in sympathetic tone. This may adversely affect cardiac autonomic control. We investigated the changes in cardiac autonomic nervous activity in relation to disease severity in patients with PAH. In 48 patients with PAH (median World Health Organization class III, pulmonary artery pressure 52+/-14 mmHg, pulmonary vascular resistance 1,202+/-718 dyn x s x cm(-5), cardiac index 2.0+/-0.8 L x min(-1) x m(-2)) and 41 controls, cardiac autonomic nervous activity was evaluated by measurement of heart rate variability (HRV) and baroreflex sensitivity. All patients underwent cardiopulmonary exercise testing (peak oxygen uptake 13.2+/-5.1 mL x kg(-1) x min(-1), minute ventilation/carbon dioxide production slope 47+/-16). In patients with PAH, spectral power of HRV was reduced in the high-frequency (239+/-64 versus 563+/-167 ms2), low-frequency (245+/-58 versus 599+/-219 ms2) and very low-frequency bands (510+/-149 versus 1106+/-598 ms2; all p<0.05). Baroreflex sensitivity was also blunted (5.8+/-0.6 versus 13.9+/-1.2 ms x mmHg(-1); p<0.01). The reduction in high-frequency (r = 0.3, p = 0.04) and low-frequency (r = 0.33, p = 0.02) spectral power and baroreflex sensitivity (r = 0.46, p<0.01) was related to the reduction in peak oxygen uptake. Patients with PAH have a marked alteration in cardiac autonomic control that is related to exercise capacity and may, therefore, serve as an additional marker of disease severity.

Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension.

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.

[Pulmonary hypertension in hereditary haemorrhagic teleangiectasia (Rendu-Osler-Weber disease). Progression over 10 years]. / Pulmonale Hypertonie bei hereditärer hämorrhagischer Teleangiektasie (Morbus Osler). Verlauf über 10 Jahre.

HISTORY: 10 years ago a now 49-year-old woman with Render-Osler-Weber disease showed unspecific symptoms of nausea, and general unwellness. Pulmonary manifestation of the disease was accompanied by pulmonary hypertension. INVESTIGATION: Teleangiectasia of the tongue and pharynx as well as of the mucosa of mouth and nose were observed. Fixed-splitting of the second heart sound with accentuated pulmonary component and a 2/6 systolic murmur over the tricuspid valve were heard. In addition, a murmur was heard dorsal over the right lung's lower lobe. Apart from minor oedema of both ankles, the physical status was not remarkable. Echocardiography showed dilatation of the right ventricle and a minor regurgitation of the tricuspid valve. The computed tomography showed dilatation of the pulmonary arteries as well as an arteriovenous malformation in the right lower lobe. Right-heart catheterisation revealed elevated pulmonary pressure. THERAPY AND FOLLOW-UP: Initial treatment with a calcium channel blocker proved insufficient and was changed to inhalative, and later to oral prostanoids. Under this treatment the cardiopulmonary state was stabilised, but episodes of epistaxis were increased. Two years after readjustment of the medication to a dual endothelin receptor antagonist, the cardiopulmonary state remains stable without significant haemorrhagic complications. CONCLUSION: Prostanoid treatment in patients with Render-Osler-Weber disease and additional pulmonary hypertension can lead to an increased risk of haemorrhagic complications. Treatment with newer medications, such as endothelin receptor antagonists, seems indicated as successfully illustrated in our case.

Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.

Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension.

STUDY OBJECTIVES: Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology that is characterized by a poor prognosis. This study was undertaken to investigate possible correlations between endothelin (ET)-1 and big ET-1 plasma levels and the severity of PPH. PATIENTS: Sixteen consecutive patients with PPH were included. INTERVENTIONS: Hemodynamics of patients with PPH were measured by right-heart catheterization, and a 6-min walk test was performed. MEASUREMENTS: Plasma levels of the biologically active peptide ET-1 and its precursor big ET-1 were determined in blood samples from the pulmonary artery, peripheral artery, and peripheral vein by radioimmunoassay. RESULTS: A strong correlation was shown between pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, cardiac index, 6-min walk data, and elevated plasma levels of big ET-1 as well as mature ET-1 plasma levels at all sites of blood sampling (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Levels of circulating ET-1 might become a prognostic marker for patients with PPH and serve as a tool for the selection of patients who may benefit from treatment with ET-receptor antagonists.

Impairment of ventilatory efficiency in heart failure: prognostic impact.

BACKGROUND: Impairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea. METHODS AND RESULTS: We investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [VO(2)max], 15.3 mL O(2) x kg(-1) x min(-1); mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of V(CO(2)) and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among VO(2)max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus V(CO(2)) slope; patients with a slope 130% (54.7%; P<0.001). CONCLUSIONS: The VE versus V(CO(2)) slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than VO(2)max.

Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension.

BACKGROUND: The continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH. METHODS AND RESULTS: In 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 microgram of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne. s(-1). cm(-5), P<0.05). Arterial blood gases remained unchanged (PaO(2) 69.3 versus 66.8 mm Hg; PaCO(2) 29.6 versus 28.8 mm Hg). Iloprost significantly (P<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL. kg(-1). min(-1)), VE-versus-V CO(2) slope (58 versus 51.4). CONCLUSIONS: The present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.

Relationship between impaired pulmonary diffusion and cardiopulmonary exercise capacity after heart transplantation.

STUDY OBJECTIVES: Diffusion impairment and reduced performance in cardiopulmonary exercise testing (CPX) have been found in patients after heart transplantation. The pathogenesis of these abnormalities is unclear. In particular, the contribution of pulmonary interstitial changes has not yet been verified. DESIGN: We analyzed pulmonary function tests, high-resolution CT (HRCT), echocardiography, left heart catheterization, and CPX in transplanted patients. PATIENTS: Forty long-term survivors were studied at a median of 47 months (range, 12 to 89 months) after heart transplantation. RESULTS: Diffusion was impaired in 40% (transfer factor for carbon monoxide) or 82.5% (carbon monoxide transfer coefficient) of the patients. Diffusion impairment was caused by a decreased diffusing capacity of the alveolar capillary membrane in 89% and/or by a decreased blood volume of the alveolar capillaries in 46% of cases. In five patients (12.5%), CT revealed interstitial lung changes. These patients did not have different values of diffusion capacity. Maximal oxygen uptake and ventilatory efficiency during exercise (minute ventilation/carbon dioxide output slope) were impaired in 92% and 46% of the cases, respectively. CONCLUSIONS: Our data show that the diffusion abnormalities are caused by an impaired diffusion status of the alveolar capillary membrane. Interstitial changes detectable in HRCT were found not to be involved in this process. The reduced performance in CPX in our long-term survivors is caused by pulmonary perfusion abnormalities and low tidal volume, which is due to the deconditioning of respiratory muscle, rather than by interstitial changes or diffusion abnormalities.

[Iloprost as inhalational and intravenous long-term treatment of patients with primary pulmonary hypertension. Register of the Berlin Study Group for Pulmonary Hypertension]]. / Iloprost als inhalative bzw. intravenöse Langzeitbehandlung von Patienten mit Primärer Pulmonaler Hypertonie. Register der Berliner Arbeitsgruppe für Pulmonale Hypertonie.

Follow-up data for 81 consecutive patients with primary pulmonary hypertension (PPH) and pulmonary hypertension related to connective tissue diseases or liver cirrhosis, entered into a multicenter registry in Berlin between 1/96 and 11/99, are described. At entry into the registry the diagnosis of PPH was known for 22 +/- 32 months. Hemodynamically, these patients were characterized by a right atrial pressure of 8.6 +/- 5 mmHg, a mean pulmonary arterial pressure of 58.9 +/- 17 mmHg, a cardiac index of 1.8 +/- 0.6 l/min/m2 and a pulmonary vascular resistance of 1574 +/- 787 dyn x s x cm-5. In about one third of the patients, a restrictive and/or obstructive pulmonary physiology was found while the majority showed signs compatible with small airway disease. Furthermore, diffusion abnormalities were found in about 65% of the patients. When added to conventional medical therapy the treatment with inhaled or continuously infused prostanoids represents a major improvement in the treatment of patients with PPH. Aerosolized iloprost therapy was started in 51 patients and was continued for 12 and 24 months in 20 and 6 patients, respectively. This therapy was well tolerated without any significant changes in pulmonary function or signs of toxicity. About 25% of these patients had to be switched to continuous intravenous therapy due to progressive clinical and hemodynamic deterioration. About two thirds of these "rescue patients" could be stabilized on intravenous therapy and discharged from the hospital. Based on the currently available evidence, the continuous infusion of prostanoids represents an important part of the standard therapy in the treatment of patients with PPH. These first long-term data on inhaled iloprost therapy in this patient group illustrate the potential value of this well-tolerated and effective treatment within the concept of a differentiated treatment plan for patients with PPH. However, the true importance of prostanoid inhalation in comparison to continuous intravenous therapy in PPH remains to be determined in randomized controlled trials.