Evaluation of a newly developed 2D parametric parenchymal blood flow technique with an automated vessel suppression algorithm in patients with chronic thromboembolic pulmonary hypertension undergoing balloon pulmonary angioplasty.

AIM: To evaluate the feasibility of two-dimensional parametric parenchymal blood flow (2D-PPBF) to quantify perfusion changes in the lung parenchyma following balloon pulmonary angioplasty (BPA) for treatment of chronic thromboembolic pulmonary hypertension. MATERIALS AND METHODS: Overall, 35 consecutive interventions in 18 patients with 98 treated pulmonary arteries were included. To quantify changes in pulmonary blood flow using 2D-PPBF, the acquired digital subtraction angiography (DSA) series were post-processed using dedicated software. A reference region of interest (ROI; arterial inflow) in the treated pulmonary artery and a distal target ROI, including the whole lung parenchyma distal to the targeted stenosis, were placed in corresponding areas on DSA pre- and post-BPA. Half-peak density (HPD), wash-in rate (WIR), arrival to peak (AP), area under the curve (AUC), and mean transit time (MTT) were assessed. The ratios of the reference ROI to the target ROI (HPDparenchyma/HPDinflow, WIRparenchyma/WIRinflow; APparenchyma/APinflow, AUCparenchyma/AUCinflow, MTTparenchyma/MTTinflow) were calculated. The relative differences of the 2D-PPBF parameters were correlated to changes in the pulmonary flow grade score. RESULTS: The pulmonary flow grade score improved significantly after BPA (1 versus 3; p<0.0001). Likewise, the mean HPDparenchyma/HPDinflow (-10.2%; p<0.0001), APparenchyma/APinflow (-24.4%; p=0.0007), and MTTparenchyma/MTTinflow (-3.5%; p=0.0449) decreased significantly, whereas WIRparenchyma/WIRinflow (+82.4%) and AUCparenchyma/AUCinflow (+58.6%) showed a significant increase (p<0.0001). Furthermore, a significant correlation between changes of the pulmonary flow grade score and changes of HPDparenchyma/HPDinflow (ρ=-0.21, p=0.04), WIRparenchyma/WIRinflow (ρ=0.43, p<0.0001), APparenchyma/APinflow (ρ=-0.22, p=0.03), AUCparenchyma/AUCinflow (ρ=0.48, p<0.0001), and MTTparenchyma/MTTinflow (ρ=-0.39, p<0.0001) could be observed. CONCLUSION: The 2D-PPBF technique is feasible for the quantification of perfusion changes following BPA and has the potential to improve monitoring of BPA.

Pulmonary hypertension in HFpEF and HFrEF: Pathophysiology, diagnosis, treatment approaches.

Pulmonary hypertension (PH) is a frequent hemodynamic condition that is highly prevalent in patients with heart failure and reduced (HFrEF) or preserved ejection fraction (HFpEF). Irrespective of left ventricular EF, the presence of PH and right ventricular (RV) dysfunction are highly relevant for morbidity and mortality in patients with heart failure. While elevated left-sided filling pressures and functional mitral regurgitation primarily lead to post-capillary PH, current guidelines and recommendations distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH), the latter being defined by a pulmonary vascular resistance (PVR) of ≥3 Wood units. Here, we describe the pathophysiology and clinical relevance of these distinct entities, and report on the diagnostic work-up including remote pulmonary artery pressure (PAP) monitoring. Furthermore, we highlight strategies to manage PH and improve RV function in heart failure, which may include optimized management of HFrEF and HFpEF (medical and interventional), sufficient volume control, catheter-based mitral valve repair, and-in selected cases-targeted PH therapy. In this context, we also highlight gaps in evidence and the need for further research.

Prolonged Mechanical Ventilation After Lung Transplantation-A Single-Center Study.

This single-center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMV was necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMV were renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82-21.29], p < 0.001), anastomotic dehiscence (OR 8.74 [95% CI 2.42-31.58], p = 0.001), autoimmune comorbidity (OR 5.52 [95% CI 1.86-16.41], p = 0.002), and postoperative neurologic complications (OR 5.03 [95% CI 1.98-12.81], p = 0.001), among others. Overall 1-year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMV and 90.0% in controls (p < 0.001). Conditional long-term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI 2.40-5.25], p < 0.001), post-LTx extracorporeal membrane oxygenation (HR 3.47 [95% CI 2.06-5.83], p < 0.001), and prolonged inotropic support (HR 1.95 [95% CI 1.39-2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMV complicated 14% of LTx procedures and, although associated with increased in-hospital mortality, outcomes among patients surviving to hospital discharge were unaffected.

[Extracorporeal membrane oxygenation : Principles and medical indications]. / Extrakorporale Membranoxygenierung : Prinzip und internistische Indikationen.

Extracorporeal membrane oxygenation (ECMO) is a special form of a miniaturized heart-lung machine with the ultimate goal to stabilize critically ill patients. Dependent on the cannulation strategy ECMO can support or replace heart and/or lung function. Medical indications and contraindications have to be evaluated thoroughly before cannulation. Moreover, before ECMO initiation a solid treatment aim has to be defined: bridge to recovery, bridge to decision, bridge to transplantation, and bridge to destination (i. e. implantation of a permanent assist device). Regarding invasiveness of the system, potential life-threatening complications, requirement of standardized monitoring of the patient and the device as well as tertiary care infrastructure, ECMO should exclusively be used in highly experienced tertiary centers.

[Riociguat: stimulator of soluble guanylate-cyclase. New mode of action for the treatment of pulmonary arterial and non operable chronic thromboembolic pulmonary hypertension]. / Riociguat: Stimulation der löslichen Guanylatzyklase. Neuer Wirkmechanismus zur Behandlung der pulmonal-arteriellen und der nicht operablen chronisch thromboembolischen pulmonalen Hypertonie.

Riociguat is the first clinically available soluble Guanylate-cyclase stimulator (sGC) and representative of a completely new class of drugs. Riociguat is approved for pulmonary arterial hypertension (PAH) and non-operable or recurrent/persistent chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, Riociguat is currently under investigation for a wider spectrum of diseases. This article focusses on its mode of action and clinical trial data. Finally, based on these data, the status of approval, as well as the costs a proposal is given how Riociguat can be integrated in the current treatment of PAH and CTEPH.

The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension.

Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy. A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3-12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease. Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan-Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (S(v,O(2))) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, S(v,O(2)) and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline. Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

[Histopathological aspects of pulmonary hypertension]. / Histopathologische Aspekte der pulmonalen Hypertonie.

In pulmonary hypertension there is a discrepancy between the dramatic but unspecific clinical presentation and the remodeling of mostly only limited segments of the vascular compartment of pulmonary parenchyma. Clinical diagnosis relies for the most part on invasive procedures, such as right heart catheterization. Therefore, morphology can provide a reliable etiopathogenetic classification only in close cooperation with the clinical partner disciplines involved. Moreover, the histopathological approach requires intimate knowledge of the vascular anatomy of the lungs and assessment of the parenchyma to be able to diagnose pulmonary hypertension and differentiate between the various types.

[Right heart failure in chronic pulmonary hypertension and acute pulmonary embolism]. / Rechtsherzversagen bei chronischer pulmonaler Hypertonie und akuter Lungenembolie.

Right-sided heart failure is a severe and often life-threatening complication of chronic pulmonary hypertension. The detection of trigger factors that induce right heart failure in previously stable patients is important to initiate a causal therapeutic strategy. Pulmonary embolism (PE) is a frequent cause of acute right heart failure and therapeutic strategies for PE are well documented in the current guidelines. Treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is surgical pulmonary endarterectomy (PEA) and patients with possible CTEPH should be referred to an experienced PEA surgeon without delay. Intensive care management for overt right heart failure is complex and includes the use of pulmonary vasodilators, individual adjustment of diuretic or volume therapy, augmentation of myocardial contractility and left ventricular afterload. Therapeutic regimens aim at optimized filling of the right ventricle, improvement of myocardial perfusion by avoiding tachycardia, elevating systemic pressure and reducing right ventricular afterload. Early communication with a specialized center for pulmonary hypertension is recommended.

Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension.

INTRODUCTION: Ambrisentan, a selective endothelin receptor antagonist has been approved in several countries for pulmonary arterial hypertension. No data have been published on the efficacy of ambrisentan on improvement of exercise capacity in patients with portopulmonary hypertension (PoPH). PATIENTS AND METHODS: We retrospectively analyzed the safety and efficacy of ambrisentan in patients with PoPH in four German university hospitals. RESULTS: 14 patients with moderate to severe PoPH were included. The median follow-up was 16 months (IQR, 12 - 21). 6 minute walk tests after 6 and 12 months improved from 376 meters (IQR, 207 - 440) at baseline to 415 meters (IQR, 393 - 475; p = 0.011) and 413 meters (IQR, 362 - 473, p = 0.005), respectively. WHO- functional class after 1 year of therapy with ambrisentan also improved significantly (p = 0.014). No significant changes in blood gas analysis and liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) during therapy with ambrisentan were detectable. CONCLUSIONS: The present study demonstrates significant improvement of exercise capacity and clinical symptoms without relevant safety concerns during ambrisentan treatment in patients with PoPH.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Extracorporeal membrane oxygenation in nonintubated patients as bridge to lung transplantation.

We report on the use of veno-arterial extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation in awake and spontaneously breathing patients. All five patients described in this series presented with cardiopulmonary failure due to pulmonary hypertension with or without concomitant lung disease. ECMO insertion was performed under local anesthesia without sedation and resulted in immediate stabilization of hemodynamics and gas exchange as well as recovery from secondary organ dysfunction. Two patients later required endotracheal intubation because of bleeding complications and both of them eventually died. The other three patients remained awake on ECMO support for 18-35 days until the time of transplantation. These patients were able to breathe spontaneously, to eat and drink, and they received passive and active physiotherapy as well as psychological support. All of them made a full recovery after transplantation, which demonstrates the feasibility of using ECMO support in nonintubated patients with cardiopulmonary failure as a bridging strategy to lung transplantation.

Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.

[Pulmonary hypertension - historical development, current therapy and perspectives]. / Die pulmonale Hypertonie - historische Entwicklung, derzeitiger Stand der Therapie und Ausblick.

This article provides a brief overview on the history of pulmonary hypertension, starting with the first descriptions of the accompanying pulmonary vascular lesions by Ernst von Romberg and Victor Eisenmenger at the end of the 19th century. Many of the histopathological changes in the pulmonary vasculature found in the various forms of pulmonary hypertension had already been described in the first half of the 20th century. However, only through the pioneering work by Forssmann and Cournand during the middle of the 20th century was it finally possible to catheterise the right ventricle and the pulmonary arteries. After this it became feasible to study the clinical spectrum of the various forms of pulmonary hypertension as well as the effects of therapeutic interventions. Early treatment attempts with vasodilators, however, were not successful. Intravenous prostacyclin, used to treat some forms of pulmonary hypertension since 1980, became the first effective treatment. Since that time, our understanding of the pathogenesis of pulmonary hypertension has increased substantially, as has the number of effective therapies, at least for some forms of pulmonary hypertension. Many aspects of the disease, however, remain poorly understood and a cure is still not achievable for the majority of the affected patients.

[Pulmonary complications of liver cirrhosis: hepatopulmonary syndrome, portopulmonary hypertension and hepatic hydrothorax]. / Pulmonale Komplikationen der Leberzirrhose: hepatopulmonales Syndrom, portopulmonale Hypertonie und hepatischer Hydrothorax.

Hepatopulmonary syndrome, portopulmonary hypertension and hepatic hydrothorax are typical pulmonary complications in patients with liver cirrhosis. Whereas hepatopulmonary syndrome and portopulmonary hypertension represent pulmonary vascular diseases, the development of hepatic hydrothorax is associated with the presence of ascites and phrenic lesions. For severe hepatopulmonary syndrome and refractory hepatic hydrothorax, liver transplantation is the treatment of choice. In severe portopulmonary hypertension specific medical treatment is indicated. In selected patients, beside intravenous prostanoids, oral endothelin receptor antagonists and phosphodiesterase type-5 inhibitors are possible treatment options.

Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device.

We describe a novel technique of pumpless extracorporeal life support in four patients with cardiogenic shock due to end-stage pulmonary hypertension (PH) including patients with veno-occlusive disease (PVOD) using a pumpless lung assist device (LAD). The device was connected via the pulmonary arterial main trunk and the left atrium, thereby creating a septostomy-like shunt with the unique addition of gas exchange abilities in parallel to the lung. Using this approach, all four patients were successfully bridged to bilateral lung transplantation and combined heart-lung transplantation, respectively. Although all patients presented in cardiogenic shock, hemodynamic unloading of the right ventricle using the low-resistance LAD stabilized the hemodynamic situation immediately so that no pump support was subsequently required.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension.

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

[Pulmonary arterial hypertension in collagenoses]. / Pulmonal arterielle Hypertonie bei Kollagenosen.

Pulmonary arterial hypertension is a rare disease of small pulmonary arteries of unknown origin characterised by endothelial dysfunction and cellular proliferation throughout all vessel layers, resulting in progressively elevated pulmonary arterial resistance with increasing right heart strain and finally right heart failure. The condition may develop in connective tissue diseases with variable frequency leading to a substantial worsening of prognosis. However, the spectrum of therapeutic options has broadened significantly in recent years. Several compounds have gained approval that act mainly as pulmonary vasodilators. Further drugs are under investigation, some of which target pulmonary vascular remodeling. Echocardiography remains the primary examination for disease detection. To classify pulmonary hypertension definite hemodynamic evaluation by means of right heart catheterisation and a thorough differential diagnosis are essential to provide the basis for further treatment. For differential therapy and assessment of follow-up profound knowledge is required, pointing to the need for close cooperation with specialised centres.

The search for an oral prostanoid to treat pulmonary arterial hypertension continues. Are we getting any closer?

Among the most commonly used therapies to treat pulmonary arterial hypertension (PAH) are the prostanoids. Epoprostenol, a relatively effective therapy for PAH, has its limitations, which are largely attributable to its pharmacokinetic properties and its requirement for intravenous administration. The development of an equally effective oral prostanoid would be an important advance in the PAH armamentarium. An early generation oral prostanoid, beraprost, was previously demonstrated to have modest, transient clinical benefits, but at the cost of a high proportion of intolerable side effects. TRK-100STP is a newer generation oral prostanoid currently under clinical investigation.

Endothelin receptor antagonists in pulmonary arterial hypertension.

The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.