[Dyspnoea in Patients with Pulmonary Hypertension (PH) - a Survey in Spezialized German PH Centres]. / Dyspnoe bei Patienten mit Pulmonaler Hypertonie (PH) - Ergebnisse einer Befragung in deutschen PH-Zentren.

Dyspnoea is the predominant symptom in patients with pulmonary hypertension (PH) at diagnosis. However, since dyspnoea is nonspecific and often occurs in a number of common diseases, the presence of PH can easily be underdiagnosed.In addition, this symptom underlies a high variability in the subjective perception, therefore further diagnostic procedures are often delayed by the patients.A survey of the incidence and severity of dyspnoea in 372 patients with PAH was conducted by questionnaire in German centres. Age, sex distribution and the range of comorbidities corresponded to the findings of national and international registries.Approximately 99 % of patients reported the presence of dyspnoea on exertion, even at low loads.Remarkably, in 13 % of patients dyspnoea occurs as a paroxysmal symptom, which may lead to the differential diagnosis of bronchial asthma. In addition, the patients who were being followed in specialized PH centres reported an increase in dyspnoea during the last year.The results of the survey on the incidence of dyspnoea in patients with PAH are consistent with the findings of international studies.

[Early diagnosis and therapy in pulmonary hypertension--aspects of a vision]. / Die frühe Diagnose und Therapie der pulmonalen Hypertonie--Aspekte einer Vision.

In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure ≥ 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking.

[The Study of Health in Pomerania (SHIP) reference values for cardiopulmonary exercise testing]. / Referenzwerte für die Spiroergometrie - Ergebnisse der Study of Health in Pomerania (SHIP).

The interpretation of gas exchange measured by cardiopulmonary exercise testing (CPET) depends on reliable reference values. Within the population based Study of Health in Pomerania (SHIP) CPET was assessed in 1706 volunteers. The assessment based on symptom limited exercise tests on a bicycle in a sitting position according to a modified Jones protocol. CPET was embedded in an extensive examination program. After the exclusion of active smokers and volunteers with evidence of cardiopulmonary and musculoskeletal disorders the reference population comprised 616 healthy subjects (333 women) aged 25 to 85 years. Reference equations including upper and/or lower limits based on quantile regression were assessed. All values were corrected for the most important influencing factors.This study provides reference equations for gas exchange and exercise capacity assessed within a population in Germany.

[Pulmonary hypertension: hemodynamic evaluation: hemodynamic evaluation ­ recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie: invasive Diagnostik: Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) have been adopted for Germany. Invasive hemodynamic data obtained by right heart catheterization are essential to confirm the diagnosis, test vasoreactivity, assess severity and guide therapy in PH patients. The definition of PH is resting on a mean pulmonary artery pressure ≥ 25 mm Hg obtained by right heart catheterization. Furthermore, a pulmonary capillary wedge pressure > 15 mm Hg excludes pre-capillary PH. Vasoreactivity testing is part of the diagnostic work-up in pulmonary arterial hypertension. Recent data on the use of inhaled iloprost update these guidelines and are of special importance due to the frequent diagnostic use of iloprost in Germany. Other aspects of invasive hemodynamic data in certain PH subgroups as well as their measurement and interpretation in children are discussed. Several aspects of right heart catheterization in PH justify a detailed commentary, and in some areas 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 Paediatric 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 were initiated, one of which was specifically addressing the invasive hemodynamic evaluation of patients with PH. This commentary summarizes the results and recommendations of this working group.

Resting alveolar gas tensions as a mortality prognosticator in chronic heart failure.

BACKGROUND: Increased end-tidal oxygen (ET-O(2)) and decreased end-tidal carbon dioxide (ET-CO(2)) gas tensions are noninvasively measurable correlates of ventilatory inefficiency, leading to increased ventilatory requirements relative to gas exchange among patients with chronic heart failure (CHF). We investigated the prognostic value of ET-O(2) and ET-CO(2) as predictors of CHF mortality. METHODS: We measured resting ET-O(2) and ET-CO(2) electrochemically in 134 patients with symptomatic CHF in the supine position. We used Kaplan-Meier analysis, Cox proportional hazard models, and receiver operating characteristic curves to test our hypothesis. RESULTS: At a median follow-up of 16.5 months, 32 patients had died. ET-O(2) levels were increased (P = .001) and ET-CO(2) levels decreased (P = .002) with increased New York Heart Association class (I-IV). Survivors showed lower ET-O(2) (121 vs 118 mm Hg; P = .021) and higher ET-CO(2) (33.2 vs 32.1 mm Hg; P = .032) levels than nonsurvivors. Patients with ET-O(2) values ≥121 mm Hg and/or ET-CO(2) values <31 mm Hg had an increased risk of death with hazard ratios of 2.93 (95% confidence interval [CI], 1.43-6.01) and 2.47 (95% CI, 1.23-4.97), respectively. Kaplan-Meier estimates for follow-up mortality with ET-O(2) ≥121 mm Hg and/or ET-CO(2) <31 mm Hg were 83.8% (vs 60.1%; P = .0014) and 80.3% (vs 60.2%; P = .0061), respectively. Areas under the receiver operating characteristic curves for prediction of death with ET-O(2) and ET-CO(2) were both significant and similar to that of echocardiographic left ventricular function. CONCLUSIONS: In CHF, high levels of ET-O(2) and low levels of ET-CO(2) are associated with increased mortality. We suggest that the measurements may be useful prognostic markers for risk stratification.

[Pulmonary hypertension in left heart disease]. / Pulmonale Hypertonie bei Linksherzerkrankungen.

Pulmonary hypertension (PH) is a relatively common hemodynamic finding in patients with left-sided heart disease and is usually associated with increased morbidity and mortality. However, so far no study has demonstrated long-term benefit from drugs specifically designed to improve pulmonary hemodynamics. There are currently no consensus recommendations on the management of PH in patients with chronic left heart failure. Most importantly, the underlying cause of left heart disease should be treated first. While previous studies with endothelin receptor antagonists or epoprostenol have been disappointing, initial promising results have been published for the phosphodiesterase-5 inhibitor sildenafil. Following acute administration and with chronic therapy for up to 6 months sildenafil improved hemodynamic parameters and exercise capacity in patients with PH and chronic left heart failure. Until the results from larger randomized controlled trials become available, the treatment of chronic left heart failure should follow the current guidelines.

[International, prospective register for the documentation of first-line and maintenance therapy in patients with pulmonary hypertension (CompERA-XL)]. / Internationales, prospektives Register zur Erfassung der Initial- und Dauertherapie von Patienten mit pulmonaler Hypertonie (CompERA-XL).

In view of the manifold options for mono- and combination therapy that have now emerged for patients with pulmonary (arterial) hypertension (PAH/PH), controlled clinical trials can only provide part of the information needed for optimal management. In order to gather adequate data on PAH/PH treatment in routine clinical care, the ongoing CompERA-XL register prospectively documents consecutive patients with newly initiated treatment of PAH/PAH since May 2007. The internet-based register fulfils high quality standards through several measures (minimum centre contribution of at least 10 patients per year, automated plausibility checks of data at entry, queries, monitoring with source data verification). It can be applied, among further purposes, for quality assurance: individual centers can confidentially compare their results with the combined outcome of other centers and the recommendations from guidelines. The register, currently active in 7 countries, presently follows up 785 patients with any kind of treatment for PH/PAH (now at 626 patient years). It is expected that the register contributes to optimization of specific drug therapy for PAH and PH.

Bleeding events in pulmonary arterial hypertension.

Despite limited evidence from clinical studies, anticoagulant drugs such as vitamin K antagonists (VKA) (e.g., warfarin or phenprocoumon) are widely used in the background treatment of patients with pulmonary arterial hypertension (PAH). According to current guidelines, they are generally accepted as efficacious drugs, although their efficacy is neither supported by randomised controlled trials, nor formally approved by regulatory agencies for use in the specific PAH indication. The use of these drugs is not without problems, as a paradoxical situation has to be managed in the treatment of this condition. On one hand, thrombosis is one of the key pathophysiologic features of PAH (besides vasoconstriction, proliferation and inflammation). On the other hand, the incidence of bleeding events is increased in PAH patients. This applies particularly to PAH that is related to connective tissue diseases, congenital heart disease and chronic thromboembolic pulmonary hypertension. In patients receiving VKA, caution must be observed in particular when concomitantly using prostanoids or sildenafil. Similarly, VKA doses have to be adjusted according to the labelling when using sitaxentan concomitantly. Regular International Normalized Ratio monitoring contributes to the safety of PAH patients on VKA.

Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study.

Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. The aim of the present study was to acquire a comprehensive set of reference values for cardiopulmonary responses to exercise and to evaluate possible associations with sex, age and body mass index (BMI). A standardised progressive incremental exercise protocol on a cycle ergometer was applied to 1,708 volunteers of a cross-sectional epidemiologic survey, called "Study of Health in Pomerania". Individuals with cardiopulmonary disorders, or echocardiographic or lung function pathologies, were excluded. The influence of potential confounding factors, such as smoking, taking beta-blockers, hypertension, diastolic dysfunction, BMI and physical activity, were analysed for their influencing power. Reference values of CPET parameters were determined by regression analyses. Of the volunteers, 542 current smokers and obese individuals were excluded for not being representative of a healthy population. The final sample size was 534 (253 males), with age 25-80 yrs. The current study provides a representative set of reference values for CPET parameters based on age and weight. Sex and age have a significant influence on exercise parameters. While addressing the problem of a selection bias, the current study provides the first comprehensive set of reference values obtained in a large number of healthy volunteers within a population-based survey.

Pulmonary interstitial and vascular abnormalities following cardiac transplantation.

Impairment of pulmonary diffusion (KCO) is frequently seen in patients following orthotopic heart transplantation (HTX). To assess potential histomorphological pulmonary causes of KCO abnormalities, we evaluated tissue samples from 73 patients who succumbed after HTX in the presence of KCO abnormalities, excluding those with infectious or primary pulmonary causes of death. In 97% of subjects, we observed considerable histomorphological changes in interstitial or vascular tissue or both. In 32% of samples, interstitial changes (eg, cell proliferation or fibrosis) were accompanied by vascular abnormalities, whereas more than two-thirds of the patients showed alterations in one of the two conditions. Hemosiderin-laden macrophages were observed in 48% of subjects. The mean alveolar-capillary wall thickness was significantly increased to 9.9 +/- 4.2 mum. The time of survival after HTX was not correlated with the incidence of pathological findings. The described vascular and interstitial pulmonary changes as well as the increased membrane thickness may cause the persistent impairment of KCO after HTX.

[Combination therapy in patients with pulmonary arterial hypertension]. / Medikamentöse Kombinationsbehandlung bei Patienten mit Pulmonal arterieller Hypertonie.

Despite recent remarkable efforts in the medical treatment options of patients with pulmonary arterial hypertension (PAH) a considerable number of patients need escalations to improve disease related symptoms and pulmonary hemodynamics. Most of the pulmonary vascular vasodilators have been approved in its potency as an initial and sole medical option. However, there is increasing scientific evidence on the reliability, safety and effectiveness of possible combinations. This paper reviews the current scientific literature about medical escalations and combination therapy in patients with PAH.

Screening for PAH in patients with systemic sclerosis: focus on Doppler echocardiography.

It is well established that patients with CTDs such as SSc carry a considerable risk of developing pulmonary arterial hypertension (PAH). Such SSc-PAH patients have an even worse prognosis than patients with only one of these two conditions. In view of the high incidence and prevalence of PAH in SSc, and the available treatment options that improve quality of life, exercise capacity and possibly survival, systematic screening has been recommended. The present article reviews current recommendations from PAH guidelines, focusing on studies that used Doppler echocardiography for screening, and describes limitations associated with the procedure. Furthermore, characteristics and parameters used to identify patients at high risk of developing PAH are summarized.

Dual ET(A)/ET(B) vs. selective ET(A) endothelin receptor antagonism in patients with pulmonary hypertension.

Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ET(A)/ET(B) and selective ET(A) receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ET(A) receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ET(B) receptors has been more complex. It has been shown that there is a subpopulation of ET(B) receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ET(B) receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ET(A) receptor antagonism.

[Pregnancy in patients with Eisenmenger's syndrome. Experiences from Vilnius 1967-2003]. / Schwangerschaft bei Eisenmenger-Patientinnen. Erfahrungen aus Vilnius 1967-2003.

Pregnancy in patients with Eisenmengers syndrome is associated with high maternal and fetal mortality rates and effective contraception or termination of pregnancy is strongly recommended. When these patients decide to begin or continue a pregnancy against advice a coordinated multi-specialist care at a center for congenital heart disease is mandatory. So far, experience with this demanding group of patients is limited. This report reviews the outcome of 30 pregnancies in 10 patients from a group of 35 women with Eisenmengers syndrome who have been treated at the University Hospital in Vilnius, Lithuania, between 1967 and 2003. The most frequent underlying lesion was a ventricular septal defect in 5 patients, their mean age was 26.2 +/- 5,4 years and they were in functional class II or III (9/1) at the beginning of the pregnancy. In this group 13 pregnancies were terminated (43 %), 4 spontaneous abortions (13 %) occurred at less than 21 weeks of pregnancy and one stillbirth at 23 weeks of gestation. Twelve children were born alive, 10 were premature and 2 term deliveries. One maternal death occurred on the third day following an emergency delivery in week 36 and another patient decompensated immediately following delivery, but could be stabilized with intensive care therapy. During long-term follow-up all of these 9 patients were alive at 10/2003 despite a significant deterioration in functional class. These data are comparable to previously published observations in pregnant women with Eisenmengers syndrome.

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.

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.