Safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension in the Netherlands.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an emerging treatment in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED). We describe the first safety and efficacy results of BPA in the Netherlands. METHODS: We selected all consecutive patients with inoperable CTEPH and CTED accepted for BPA treatment who had a six-month follow-up in the St. Antonius Hospital in Nieuwegein and the Amsterdam University Medical Center (UMC) in Amsterdam. Functional class (FC), N­terminal pro-brain natriuretic peptide (NT-proBNP), 6­minute walking test distance (6MWD) and right-sided heart catheterisation were performed at baseline and six months after last BPA. Complications for each BPA procedure were noted. RESULTS: A hundred and seventy-two BPA procedures were performed in 38 patients (61% female, mean age 65 ± 15 years). Significant improvements six months after BPA treatment were observed for functional class (63% FC I/II to 90% FC I/II, p = 0.014), mean pulmonary artery pressure (-8.9 mm Hg, p = 0.0001), pulmonary vascular resistance (-2.8 Woods Units (WU), p = 0.0001), right atrial pressure (-2.0 mm Hg, p = 0.006), stroke volume index (+5.7 ml/m2, p = 0.009) and 6MWD (+48m, p = 0.007). Non-severe complications occurred in 20 (12%) procedures. CONCLUSIONS: BPA performed in a CTEPH expert centre is an effective and safe treatment in patients with inoperable CTEPH.

Using patient data to optimize an expert-based guideline on convalescence recommendations after gynecological surgery: a prospective cohort study.

BACKGROUND: Convalescence advice is often based on tradition and anecdote from health care providers, rather than being based on experiences from patients themselves. The aim of this study was to analyse recovery in terms of resumption of various daily activities including work, following different laparoscopic and abdominal surgery in order to optimize an expert-based guideline on convalescence recommendations. METHODS: This is a prospective cohort study conducted in nine general and one university hospital in the Netherlands. Women aged 18-65 years and scheduled for a hysterectomy (laparoscopic, vaginal, abdominal) and/or laparoscopic adnexal surgery (n = 304) were eligible to participate. Preoperatively, participants were provided with tailored expert-based convalescence recommendations on the graded resumption of several daily activities including sitting, standing, walking, climbing stairs, bending, lifting, driving, cycling, household chores, sport activities and return to work (RTW). Postoperatively, time until the resumption of these activities was tracked. Convalescence recommendations were considered correct when at least 25% and less than 50% of the women were able to resume an activity before or at the recommended recovery time. RESULTS: There was a wide variation in the duration until the resumption of daily activities within and between groups of patients undergoing different types of surgery. Recovery times lengthened with increasing levels of physical burden as well as with increasing levels of invasiveness of the surgery. For the majority of activities actual recovery times exceeded the recovery time recommended by the expert panel. CONCLUSIONS: This study provided insight in the resumption of daily activities after gynecological surgery and the adequacy of an expert-based convalescence guideline in clinical practice. Patient data was used to optimize the convalescence recommendations. TRIAL REGISTRATION: Dutch trial registry, NTR2087 (August 2009) and NTR2933 (June 2011).

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

Platypnoea-orthodeoxia syndrome, an underdiagnosed cause of hypoxaemia: four cases and the possible underlying mechanisms.

Cardiac platypnoea-orthodeoxia syndrome (POS) is a position-dependent condition of dyspnoea and hypoxaemia due to right-to-left shunting. It often remains unrecognised in clinical practice, possibly because of its complex underlying pathophysiology. We present four consecutive patients with POS and patent foramen ovale (PFO) who underwent a successful percutaneous PFO closure, describe the mechanism of their POS and provide a review of the literature.

Pressure-overload-induced right heart failure.

Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure.

Prediction of time to return to work after gynaecological surgery: a prospective cohort study in the Netherlands.

OBJECTIVE: To measure the impact of the level of invasiveness of gynaecological procedures on time to full Return to Work (RTW) and to identify the most important preoperative sociodemographic, medical and work-related factors that predict the risk of prolonged sick leave. DESIGN: Prospective cohort study. SETTING: Dutch university hospital. POPULATION: A total of 148 women aged 18-65 years scheduled for gynaecological surgery for benign indications. METHODS: A questionnaire regarding the surgical procedure as well as perioperative and postoperative complications was completed by the attending resident at baseline and 6 weeks after surgery. All other outcome measures were assessed using self-reported patient questionnaires at baseline and 12 weeks post-surgery. The follow-up period was extended up to 1 year after surgery in women failing to return to work. Surgical procedures were categorised into diagnostic, minor, intermediate and major surgery. MAIN OUTCOME MEASURES: Time to RTW and important predictors for prolonged sick leave after surgery. RESULTS: Median time to RTW was 7 days (interquartile range [IQR] 5-14) for diagnostic surgery, 14 days (IQR 9-28) for minor surgery, 60 days (IQR 28-101) for intermediate surgery and 69 days (IQR 56-135) for major surgery. Multivariable analysis showed a strongest predictive value of RTW 1 year after surgery for level of invasiveness of surgery (minor surgery hazard ratio [HR] 0.51, 95% CI 0.32-0.81; intermediate surgery HR 0.20, 95% CI 0.12-0.34; major surgery HR 0.09, 95% CI 0.06-0.16), RTW expectations before surgery (HR 0.55, 95% CI 0.36-0.84), and preoperative functional status (HR 1.09, 95% CI 1.04-1.13). A prediction model regarding the probability of prolonged sick leave at 6 weeks was developed, with a sensitivity of 89% and a specificity of 86%. CONCLUSIONS: RTW often takes a long time, especially after intermediate and major surgery. This study reveals important predictors for prolonged sick leave and provides a prediction model for the risk of sick leave extending 6 weeks after benign gynaecological surgery in the Netherlands.

A personalised eHealth programme reduces the duration until return to work after gynaecological surgery: results of a multicentre randomised trial.

OBJECTIVE: To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery. DESIGN: Randomised multicentre trial that ran from March 2010 until September 2011. SETTING: Secondary care in seven general and university hospitals in The Netherlands. POPULATION: A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication. METHODS: The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre- and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website. MAIN OUTCOME MEASURES: The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity. RESULTS: In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group. CONCLUSIONS: The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain.

Process evaluation of a multidisciplinary care program for patients undergoing gynaecological surgery.

PURPOSE: This study describes the process evaluation of an innovative multidisciplinary care program for patients undergoing benign gynaecologic surgery. This care program aims at improving recovery and preventing delayed return to work and consists of two steps: (1) an interactive e-health intervention for all participants, and (2) integrated clinical and occupational care management for those participants whose sick leave exceeds 10 weeks. METHODS: Eligible for this study were employed women aged between 18-65 years scheduled for a laparoscopic adnexal surgery and/or hysterectomy. Data were collected from patients, their supervisors and their gynaecologists, by means of electronic questionnaires during a 6 month follow-up period and an automatically generated, detailed weblog of the patient web portal ( www.ikherstel.nl ). Investigated process measures included: reach, dose delivered, dose received, and fidelity. In addition, attitudes towards the intervention were explored among all stakeholders. RESULTS: 215 patients enrolled in the study and accounted to a reach of 60.2 % (215/357). All intervention group patients used their account at least once and total time spent on the patient web portal was almost 2 h for each patient (median 118 min, IQR 64-173 min). Most patients visited the website several times (median 11 times, IQR 6-16). Perceived effectiveness among patients was high (74 %). In addition, gynaecologists (76 %) and employers (61 %) were satisfied with the web portal as well. Implementation of the second step of the intervention was suboptimal. Motivating patients to consent to additional guidance and developing an accurate return-to-work-prognosis were two important obstacles. CONCLUSIONS: The results of this study indicate good feasibility for implementation on a broad scale of the e-health intervention for patients undergoing benign gynaecological surgery. To enhance the implementation of the second step of the perioperative care program, adaptations in the integrated care protocol are needed.

Low nailfold capillary density in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: biomarker of clinical outcome?

Nailfold capillary density is lower in patients with pulmonary arterial hypertension (PAH). It is unclear whether this observation signifies a unique systemic manifestation of PAH, or reflects microcirculatory dysfunction secondary to pulmonary hypertension (PH). Capillary density and loop dimensions were measured by nailfold-capillaroscopy (NC) in 30 PAH (23 idiopathic, or iPAH, 7 hereditary, or hPAH), 17 chronic thromboembolic PH (CTEPH) patients and 48 controls. NC-Measurements were repeated after pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) in CTEPH patients. We examined whether NC-measurements were related to markers of disease severity and predictive of time to clinical worsening (TTCW) as tested by univariate linear/logistic regression and cox-regression analysis, respectively. Capillary density was significantly lower in PAH (7.5 ± 1.1, p < 0.001) and in CTEPH (8.4 ± 1.5, p < 0.001) compared to asymptomatic controls (10.3 ± 1.0 capillaries/mm). Capillary density was similar in iPAH and hPAH and unrelated to hemodynamics in either PAH or CTEPH. A lower capillary density was predictive of clinical worsening in PAH (p 0.05). After normalization of pulmonary artery pressures by PEA or BPA, capillary density remained reduced in CTEPH patients. Capillary loop apex, capillary and venous- and arterial limb diameter were increased in patients with PAH and CTEPH compared to controls. Nailfold capillary density is reduced to a similar extent in iPAH, hPAH and CTEPH. Normalization of hemodynamics by PEA or BPA does not lead to a restoration of capillary density in CTEPH. Capillary dimensions were increased in both patients with PAH and CTEPH. Lower capillary density was predictive of clinical worsening in PAH. Our findings indicate that a loss of peripheral capillaries is not specific to PAH and is not related to the hemodynamic disturbance per se, but that shared mechanisms may account for a simultaneous development of a systemic microangiopathy and pulmonary vascular remodeling.

Diaphragm muscle fiber function and structure in humans with hemidiaphragm paralysis.

Recent studies proposed that mechanical inactivity of the human diaphragm during mechanical ventilation rapidly causes diaphragm atrophy and weakness. However, conclusive evidence for the notion that diaphragm weakness is a direct consequence of mechanical inactivity is lacking. To study the effect of hemidiaphragm paralysis on diaphragm muscle fiber function and structure in humans, biopsies were obtained from the paralyzed hemidiaphragm in eight patients with hemidiaphragm paralysis. All patients had unilateral paralysis of known duration, caused by en bloc resection of the phrenic nerve with a tumor. Furthermore, diaphragm biopsies were obtained from three control subjects. The contractile performance of demembranated muscle fibers was determined, as well as fiber ultrastructure and morphology. Finally, expression of E3 ligases and proteasome activity was determined to evaluate activation of the ubiquitin-proteasome pathway. The force-generating capacity, as well as myofibrillar ultrastructure, of diaphragm muscle fibers was preserved up to 8 wk of paralysis. The cross-sectional area of slow fibers was reduced after 2 wk of paralysis; that of fast fibers was preserved up to 8 wk. The expression of the E3 ligases MAFbx and MuRF-1 and proteasome activity was not significantly upregulated in diaphragm fibers following paralysis, not even after 72 and 88 wk of paralysis, at which time marked atrophy of slow and fast diaphragm fibers had occurred. Diaphragm muscle fiber atrophy and weakness following hemidiaphragm paralysis develops slowly and takes months to occur.

Iron deficiency is common in idiopathic pulmonary arterial hypertension.

The aims of this study were to assess the prevalence of iron deficiency in idiopathic pulmonary arterial hypertension (IPAH) and investigate whether oral iron supplementation has effects in iron-deficient patients. Iron parameters were measure for all IPAH patients attending our centre (VU University Medical Center, Amsterdam, the Netherlands) between May 2009 and February 2010. Iron data were related to clinical parameters, including 6-min walking distance (6MWD), and haemodynamic parameters measured during right heart catheterisation. In a subset of iron-deficient patients, the uptake of iron from the bowel was studied after administering oral iron for 4 weeks. Iron deficiency was found in 30 (43%) out of 70 patients. 6MWD was reduced in iron-deficient patients compared with iron-sufficient patients (mean±sd 390±138 versus 460±143 m; p<0.05) irrespective of the existence of anaemia. In a subset of 18 patients that received oral iron, ferritin levels were significantly increased, although eight patients only slightly increased their iron storage. This study shows that iron deficiency is frequently present in IPAH and is associated with a lower exercise capacity. The small response to oral iron in 44% of the treated patients suggests impaired iron absorption in these patients.

Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target.

Iron deficiency is known to be common and detrimental in chronic left heart failure, where parenteral iron treatment has been shown to improve exercise capacity, New York Heart Association functional class and patient wellbeing. There is now increasing interest in the role of iron in the natural history of pulmonary arterial hypertension (PAH). Iron availability influences the pulmonary vasoconstrictor response to hypoxia and accumulating evidence indicates that iron deficiency is prevalent in idiopathic and heritable forms of PAH, iron status being related to exercise capacity, symptoms and poorer survival in patients with idiopathic PAH (IPAH). Potential mechanisms behind iron deficiency in IPAH include inhibition of dietary iron uptake by the master iron regulator hepcidin. High hepcidin levels underlie the anaemia of chronic disease. Possible stimuli of the observed high levels of hepcidin in IPAH include dysfunctional bone morphogenetic protein receptor type II signalling and inflammation. Iron status may influence outcomes through modulation of the pulmonary circulation as well as myocardial and skeletal muscle function. Two parallel studies, from our centre (Hammersmith Hospital, London, UK) and others in the UK and Amsterdam (the Netherlands), investigating the safety and potential benefit of iron supplementation in patients with PAH are currently under way.

Multidisciplinary convalescence recommendations after gynaecological surgery: a modified Delphi method among experts.

OBJECTIVE: To generate structured detailed uniform convalescence recommendations after gynaecological surgery by a modified Delphi method amongst experts and a representative group of physicians. DESIGN: Modified Delphi study. SETTING: Expert physicians recruited by their respective medical boards and employed at different hospitals, doctor's surgeries and healthcare services. POPULATION: Twelve experts (five gynaecologists, two general practitioners [GPs] and five occupational physicians [OPs]) and a representative sample of 63 medical doctors. METHODS: Multidisciplinary detailed recommendations for graded resumption of relevant activities after uncomplicated hysterectomy (laparoscopic supracervical, total laparoscopic/laparoscopic-assisted, vaginal and abdominal hysterectomies) and laparoscopic adnexal surgery were developed. Recommendations were based on a literature review and a modified Delphi procedure among 12 experts, recruited in collaboration with the participating medical boards of gynaecologists, GPs and OPs. MAIN OUTCOME MEASURES: A multidisciplinary consensus of at least 67% on the relevant detailed convalescence recommendations in relation to hysterectomy and laparoscopic adnexal surgery. RESULTS: Out of initially 65 activities, the expert panel judged 38 activities relevant for convalescence recommendations. Consensus for all activities was achieved after four Delphi rounds and two group discussions. The recommendations were judged as feasible by a representative sample of 26 gynaecologists, 19 GPs and 18 OPs. CONCLUSIONS: Consensus between gynaecologists, GPs and OPs was achieved on all relevant convalescence recommendations regarding hysterectomy (abdominal, vaginal and laparoscopic) and laparoscopic adnexal surgery.

Opposite effects of training in rats with stable and progressive pulmonary hypertension.

BACKGROUND: Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training. METHODS AND RESULTS: Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25+/-3.9 to 62+/-3.9 minutes; P<0.001). Moreover, capillary density increased significantly (from 1.21+/-0.12 to 1.51+/-0.07 capillaries per cardiomyocyte; P<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135+/-14 to 276+/-18 leukocytes per 1 mm(2); P<0.001). CONCLUSIONS: In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.

Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil.

Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight(-1)) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.

RC time constant of single lung equals that of both lungs together: a study in chronic thromboembolic pulmonary hypertension.

The product of resistance, R, and compliance, C (RC time), of the entire pulmonary circulation is constant. It is unknown if this constancy holds for individual lungs. We determined R and C in individual lungs in chronic thromboembolic pulmonary hypertension (CTEPH) patients where resistances differ between both lungs. Also, the contribution of the proximal pulmonary arteries (PA) to total lung compliance was assessed. Patients (n=23) were referred for the evaluation of CTEPH. Pressure was measured by right heart catheterization and flows in the main, left, and right PA by magnetic resonance imaging. Total, left, and right lung resistances were calculated as mean pressure divided by mean flow. Total, left, and right lung compliances were assessed by the pulse pressure method. Proximal compliances were derived from cross-sectional area change DeltaA and systolic-diastolic pressure difference DeltaP (DeltaA/DeltaP) in main, left, and right PA, multiplied by vessel length. The lung with the lowest blood flow was defined "low flow" (LF), the contralateral lung "high flow" (HF). Total resistance was 0.57+/-0.28 mmHg.s(-1).ml(-1), and resistances of LF and HF lungs were 1.57+/-0.2 vs. 1.00+/-0.1 mmHg.s(-1).ml(-1), respectively, P<0.0001. Total compliance was 1.22+/-1.1 ml/mmHg, and compliances of LF and HF lung were 0.47+/-0.11 and 0.62+/-0.12 ml/mmHg, respectively, P=0.01. Total RC time was 0.49+/-0.2 s, and RC times for the LF and HF lung were 0.45+/-0.2 and 0.45+/-0.1 s, respectively, not different. Proximal arterial compliance, given by the sum of main, right, and left PA compliances, was only 19% of total lung compliance. The RC time of a single lung equals that of both lungs together, and pulmonary arterial compliance comes largely from the distal vasculature.

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.

Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.