Prevalence of Anxiety and Depression in Pulmonary Hypertension and Changes during Therapy.

BACKGROUND: Pulmonary hypertension (PH) leads to reduced health-related quality of life (HRQoL). OBJECTIVE: To investigate the prevalence and course of anxiety and depression and their association with HRQoL, disease severity and survival in PH. METHODS: 131 PH patients (91 pulmonary arterial, 30 chronic thromboembolic, 10 due to lung disease; 84 female, 47 male) had repeated assessments with the Hospital Anxiety and Depression Scale (HADS), HRQoL, six-minute walk distance and WHO functional class during a mean course of 16 ± 12 months. RESULTS: Among the 49 incident and 82 prevalent PH patients, the HADS score was positive in 53%/21% (depression), 51%/24% (anxiety) and 63%/26% (total score) (all p < 0.05). The HADS score was improved at the second assessment in incident patients. The HADS score correlated with HRQoL at all consecutive assessments and with functional class until the third assessment, but not with baseline hemodynamics, age or gender. CONCLUSION: Mood disorders remain underdiagnosed in PH. The higher prevalence of anxiety/depression in incident versus prevalent patients and the improvement over time may indicate an amelioration of mood disorders after PH diagnosis and treatment.

Reactive Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-Occlusive Disease in a Patient with Repaired Scimitar Syndrome.

Pulmonary capillary hemangiomatosis (PCH) is a rare histological substrate within the spectrum of pulmonary arterial hypertension that possibly represents an unusual manifestation of pulmonary veno-occlusive disease (PVOD). One of the histological hallmarks of PCH is the proliferation of pulmonary capillaries in the alveolar septa that infiltrate adjacent structures such as bronchioles, vessels, and visceral pleura. The hyperplastic process involving the smallest vessels of the pulmonary vascular bed might reflect uncontrolled angiogenesis, but whether this vascular proliferation is idiopathic or, conversely, a reactive process remains to be elucidated. Here we discuss the pathogenesis of PCH exemplified by the first reported case of a young patient with repaired scimitar syndrome that developed unilateral PCH.

Pressure-Flow During Exercise Catheterization Predicts Survival in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension manifests with impaired exercise capacity. Our aim was to investigate whether the mean pulmonary arterial pressure to cardiac output relationship (mPAP/CO) predicts transplant-free survival in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Hemodynamic data according to right heart catheterization in patients with PAH and CTEPH at rest and during supine incremental cycle exercise were analyzed. Transplant-free survival and predictive value of hemodynamics were assessed by using Kaplan-Meier and Cox regression analyses. RESULTS: Seventy patients (43 female; 54 with PAH, 16 with CTEPH; median (quartiles) age, 65 [50; 73] years; mPAP, 34 [29; 44] mm Hg; cardiac index, 2.8 [2.3; 3.5] [L/min]/m(2)) were followed up for 610 (251; 1256) days. Survival at 1, 3, 5, and 7 years was 89%, 81%, 71%, and 59%. Age, World Health Organization-functional class, 6-min walk test, and mixed-venous oxygen saturation (but not resting hemodynamics) predicted transplant-free survival. Maximal workload (hazard ratio [HR], 0.94 [95% CI, 0.89-0.99]; P = .027), peak cardiac index (HR, 0.51 [95% CI, 0.27-0.95]; P = .034), change in cardiac index, 0.25 [95% CI, 0.06-0.94]; P = .040), and mPAP/CO (HR, 1.02 [95% CI, 1.01-1.03]; P = .003) during exercise predicted survival. Values for mPAP/CO predicted 3-year transplant-free survival with an area under the curve of 0.802 (95% CI, 0.66-0.95; P = .004). CONCLUSIONS: In this collective of patients with PAH or CTEPH, the pressure-flow relationship during exercise predicted transplant-free survival and correlated with established markers of disease severity and outcome. Right heart catheterization during exercise may provide important complementary prognostic information in the management of pulmonary hypertension.

Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry.

BACKGROUND: Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. METHODS AND RESULTS: A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90-95), 91% (95% CI, 87-93), and 89% (95% CI, 86-92) in operated patients (n=404), and only 88% (95% CI, 83-91), 79% (95% CI, 74-83), and 70% (95% CI, 64-76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension-targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49-11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76-12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95-1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20-1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36-6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18-3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension-targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. CONCLUSIONS: The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.

Disease-Targeted Treatment Improves Cognitive Function in Patients with Precapillary Pulmonary Hypertension.

BACKGROUND: Patients with pulmonary hypertension (PH) may suffer from cognitive deficits that potentially relate to reduced oxygen delivery and cerebral tissue oxygenation (CTO). OBJECTIVE: To evaluate the hypothesis that cognitive function improves with therapy, along with improved CTO. METHODS: Twenty incident patients with arterial or chronic thromboembolic PH had CTO monitoring by near-infrared spectroscopy during diagnostic right heart catheterization. Cognitive tests [Trail Making Tests (TMTs), Victoria Stroop tests and the Five-Point Test (5PT)], the 6-min walk distance (6MWD) test, New York Heart Association (NYHA) class and health-related quality of life (HRQoL) were assessed and repeated after 3 months of disease-targeted medication. RESULTS: At baseline, 45% of PH patients had cognitive deficits. At 3 months, the patients had improved on the TMT A and the Stroop 2 test [37 s (27; 55) versus 30 s (24; 42), p < 0.05, and 18 s (16; 22) versus 16 s (15; 20), p < 0.01], whereas CTO remained unchanged. Arterial oxygen saturation, NYHA class, 6MWD and HRQoL had also improved. Baseline CTO was the strongest predictor of cognitive function, even in multivariate analysis including age, 6MWD and HRQoL. Improvements in cognitive function were not associated with changes in CTO. CONCLUSIONS: In patients with PH, 3 months of disease-targeted medication resulted in better cognitive function. Although CTO was the strongest predictor of cognitive function at baseline, it did not change during target therapy. The results of this pilot study should be confirmed in an adequately powered controlled trial.

Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease.

OBJECTIVE: Validated methods for the screening and early diagnosis of systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) are needed. The aim of this study was to evaluate the performance of pulmonary function tests (PFTs) compared with that of high-resolution computed tomography (HRCT) of the chest for the detection of SSc-related ILD in clinical practice, and to identify predictors of lung involvement that is functionally occult but significant on HRCT. METHODS: Prospectively enrolled patients with SSc were assessed according to the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research standards. The assessment included PFTs and HRCT. The HRCT images were evaluated in a blinded manner by 2 experienced radiologists. The performance parameters of PFTs for the diagnosis of SSc-related ILD were calculated. Predictors of significant ILD as determined by HRCT in patients with normal forced vital capacity (FVC) values were identified through logistic regression. RESULTS: Among the 102 patients, 64 (63.0%) showed significant ILD on HRCT, while only 27 (26.0%) had an FVC <80% of predicted, and 54 (53.0%) had a decrease in the results of at least 1 PFT. Forty (62.5%) of 64 patients with significant ILD on HRCT had a normal FVC value, translating into a high false-negative rate. Notably, 5 of 40 patients with a normal FVC value had severe, functionally occult lung fibrosis; in 2 of these patients, the results of all of the PFTs were within normal limits. Patients with normal FVC values despite evidence of fibrosis on HRCT more frequently had anti-Scl-70 antibodies and diffuse SSc and less frequently had anticentromere antibodies (ACAs) compared with patients with both normal FVC values and normal HRCT results. CONCLUSION: The derived evidence-based data reveal a high risk of missing significant SSc-related ILD when relying solely on PFTs. More comprehensive screening algorithms for early detection are warranted. In particular, additional imaging investigations for the early detection of SSc-related ILD should be considered in ACA-negative patients with normal FVC values.

Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Antiproliferative strategies have emerged as a potential therapeutic option for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the long-term efficacy and safety of imatinib. METHODS: This is an observational study of 15 patients with idiopathic PAH (n = 13) or PAH associated with connective tissue disease (n = 2) treated off-label with imatinib 400 mg daily. Pulmonary hypertension-specific therapy was established in all patients (triple therapy in 10, dual therapy in 3, and monotherapy in 2 patients). RESULTS: After 6 months, improvement in hemodynamics (p < 0.01), functional class (p = 0.035), and quality of life (p = 0.005) was observed. After a median follow-up of 37 months, there was a sustained improvement in functional class (p = 0.032), quality of life (p = 0.019), and echocardiographic parameters of right ventricular function (p < 0.05). Three patients (20%) presented with completely normal echocardiography, absent tricuspid regurgitation, and normal pro-brain natriuretic peptide levels, indicative of 'hemodynamic remission'. Of note, however, only 1 case was assessed by invasive hemodynamics. The overall 1- and 3-year survival was 100 and 90%, respectively. Two patients experienced a subdural hematoma (SDH), which in both cases resolved without sequelae. After careful consultation of the potential risks and benefits, all patients as well as a safety cohort of 9 subsequent cases decided to continue the imatinib therapy. After adjusting the target international normalized ratio (INR) to around 2.0, no further cases of SDH occurred during 50 patient-years. CONCLUSIONS: Long-term treatment with imatinib may improve the functional class and quality of life. Single cases might even attain hemodynamic remission. The occurrence of 5% SDH per patient-years is concerning. However, adjusting the INR to around 2.0 might obviate this complication.

Featured Article: microRNA-125a in pulmonary hypertension: Regulator of a proliferative phenotype of endothelial cells.

Vascular remodeling due to excessive proliferation of endothelial and smooth muscle cells is a hallmark feature of pulmonary hypertension. microRNAs (miRNAs) are a class of small, non-coding RNA fragments that have recently been associated with remodeling of pulmonary arteries, in particular by silencing the bone morphogenetic protein receptor type II (BMPR2). Here we identified a novel pathway involving the concerted action of miR-125a, BMPR2 and cyclin-dependent kinase inhibitors (CDKN) that controls a proliferative phenotype of endothelial cells. An in silico approach predicted miR-125a to target BMPR2. Functional inhibition of miR-125a resulted in increased proliferation of these cells, an effect that was found accompanied by upregulation of BMPR2 and reduced expression of the tumor suppressors CDKN1A (p21) and CDKN2A (p16). These data were confirmed in experimental pulmonary hypertension in vivo. Levels of miR-125a were elevated in lung tissue of hypoxic animals that develop pulmonary hypertension. In contrast, circulating levels of miR-125a were found to be lower in mice with pulmonary hypertension as compared to control mice. Similar findings were observed in a small cohort of patients with precapillary pulmonary hypertension. These translational data emphasize the pathogenetic role of miR-125a in pulmonary vascular remodeling.

Long-term data from the Swiss pulmonary hypertension registry.

BACKGROUND: Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. OBJECTIVE: To provide long-term data of the Swiss PH registry of 1998-2012. METHODS: PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. RESULTS: From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. CONCLUSION: Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A.

Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.

Effect of nocturnal oxygen and acetazolamide on exercise performance in patients with pre-capillary pulmonary hypertension and sleep-disturbed breathing: randomized, double-blind, cross-over trial.

AIM: Sleep-disturbed breathing (SDB) is common in pre-capillary pulmonary hypertension (PH) and impairs daytime performance. In lack of proven effective treatments, we tested whether nocturnal oxygen therapy (NOT) or acetazolamide improve exercise performance and quality of life in patients with pre-capillary PH and SDB. METHODS: This was a randomized, placebo-controlled, double-blind, three period cross-over trial. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo tablets each during 1 week with 1-week washout between treatment periods. Twenty-three patients, 16 with pulmonary arterial PH, 7 with chronic thromboembolic PH, and with SDB defined as mean nocturnal oxygen saturation <90% or oxygen saturation dips >10 h(-1) with daytime PaO2 ≥7.3 kPa participated. Assessments at the end of the treatment periods included a 6 min walk distance (MWD), SF-36 quality of life, polysomnography, and echocardiography. RESULTS: Medians (quartiles) of the 6 MWD after NOT, acetazolamide, and placebo were 480 m (390;528), 440 m (368;468), and 454 m (367;510), respectively, mean differences: NOT vs. placebo +25 m (95% CI 3-46, P= 0.027), acetazolamide vs. placebo -9 m (-34-17, P = 0.223), and NOT vs. acetazolamide +33 (12-45, P < 0.001). SF-36 quality of life was similar with all treatments. Nocturnal oxygen saturation significantly improved with both NOT and acetazolamide. Right ventricular fractional area change was greater on NOT compared with placebo (P = 0.042) and acetazolamide (P = 0.027). CONCLUSIONS: In patients with pre-capillary PH and SDB on optimized pharmacological therapy, NOT improved the 6 MWD compared with placebo already after 1 week along with improvements in SDB and haemodynamics. CLINICALTRIALSGOV: NTC01427192.

Effects of exercise and vasodilators on cerebral tissue oxygenation in pulmonary hypertension.

BACKGROUND: Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. OBJECTIVE: To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. METHODS: 16 patients with PH (mean pulmonary arterial pressure ≥25 mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6 min walk distance (6MWD) was measured. RESULTS: Median CTO in PH-patients at rest was 62 % (quartiles 53; 71), during exercise 60 % (53; 65); corresponding values in controls were 65 % (73; 73) (P = NS) and 68 % (66; 70) (p = .013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R (2) = .419, p < .000); in addition, the 6MWD was predicted by CTO (adjusted R (2) = .511, p < .000). CONCLUSION: In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.

Haemosiderin-laden sputum macrophages for diagnosis in pulmonary veno-occlusive disease.

AIMS: Pulmonary veno-occlusive disease (PVOD) is a rare condition of pulmonary arterial hypertension (PAH), in which post-capillary veins are affected. Since the therapeutic approach in PVOD differs from other forms of PAH, it is crucial to establish the diagnosis. Due to the fact that affected patients are often hemodynamically unstable, minimal invasive procedures are necessary for the diagnostic work-up. Chronic alveolar haemorrhage has been observed during bronchoalveolar lavage in PVOD cases. This study therefore investigates whether signs of alveolar haemorrhage can also be found in the sputum of these patients. METHODS AND RESULTS: Six patients suffering from PVOD were included in this analysis. As controls, patients with idiopathic PAH (n = 11), chronic thromboembolic PH (n = 9) and with sclerodermia-associated PH (n = 10) were assessed. Sputum from every patient was obtained by a non-invasive manner. The amount of haemosiderin-laden macrophages was determined using the Golde score. There were statistically significant more haemosiderin-laden macrophages in the sputum of patients suffering from PVOD as compared to the other groups (P<0.05). Assuming a cut-off of 200 on the Golde score, all of the 6 PVOD patients surpassed this value compared with only 1 out of the 30 cases with precapillary PH. Thus, sensitivity and specificity with respect to the diagnosis of PVOD was 100% and 97%, respectively. CONCLUSION: The content of haemosiderin-laden macrophages in the sputum of patients suffering from PVOD is significantly higher as compared to other forms of PH and may be useful in the non-invasive diagnostic work-up of these patients.

Experience with exercise right heart catheterization in the diagnosis of pulmonary hypertension: a retrospective study.

BACKGROUND: Data on exercise pulmonary hemodynamics in healthy people and patients with pulmonary hypertension (PH) are rare. We analyzed exercise right heart catheterization (RHC) data in a symptomatic collective referred with suspected PH to characterize the differential response by diagnostic groups, to correlate resting with exercise hemodynamics, and to evaluate safety. METHODS: This is a retrospective single-center study reviewing data from patients in whom an exercise RHC was performed between January 2006 and January 2013. Patients with follow-up RHC under PH -therapy were excluded. RESULTS: Data from 101 patients were analyzed, none of them had an adverse event. In 35% we detected a resting PH (27.8% precapillary, 6.9% postcapillary). Exercise PH (mean pulmonary arterial pressure (mPAP) >30 mmHg at exercise) was found in 38.6%, whereas in 25.7% PH was excluded. We found a remarkable number of exercise PH in scleroderma patients, the majority being postcapillary. 83% of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH. Patients with resting PH had worse hemodynamics and were older compared with exercise PH ones. CONCLUSION: In this real-life experience in symptomatic patients undergoing exercise RHC for suspected PH, we found that exercise RHC is safe. The facts that the vast majority of patients with mPAP-values between 20 and 24.9 mmHg at rest had exercise PH and the older age of patients with resting PH may indicate that exercise PH is a precursor of resting PH. Whether earlier treatment start in patients with exercise PH would stabilize the disease should be addressed in future studies.

Long-term effect of vasodilator therapy in pulmonary hypertension due to COPD: a retrospective analysis.

PURPOSE: Pulmonary hypertension (PH) due to COPD has dismal prognosis. We reviewed the long-term effect of PH-target therapy in severe PH-COPD. METHOD: Patients attending our PH-clinic were reviewed for PH-COPD receiving PH-target therapy. Baseline characteristics, death/transplantation until 2014, therapy, NYHA functional class, 6 min walk distance (6MWD) and oxygen saturation (SpO(2)) at baseline, 3, 6, 12 and 24 months were analysed. RESULTS: Of 48 PH-COPD identified 21 were excluded (insufficient data, comorbidity). 27 patients (7 females, 21 smokers, 23 emphysema) with median (quartiles) baseline age 70 (60; 76) years, FEV1 60 (46; 78) %, FEV1/FVC 57 (51; 64) %, DLCO 42 (36; 59) %, mean pulmonary artery pressure 39 (32;44) mmHg under inhaled iloprost (10), subcutaneous prostanoids (2), intravenous prostanoids (3), endothelin receptor antagonists (15) and phosphodiesterase-5-inhibitors (25) were included. Under therapy, NYHA functional class improved from 3.5 (3; 4) to 3 (2; 4) after 3 months and 3 (2; 3.5) after 6 months (p = .02 and .008). The 6MWD improved from 373 (236; 452) to 395 (339; 472), 414 (285; 492) and 396 (308; 497)m at 3, 6 and 12 months (p = .005, .006 and .011) with unchanged resting-SpO(2) but decreased peak-exercise SpO(2). During median follow-up of 5.9 (2.3; 8.4) years, 10 died, 2 were transplanted and 2 were lost to follow-up. Transplant-free survival at 1,2,3 years was 92,69,54 % and was similar for GOLD stages 1-4, but worse for patients with mPAP ≥40 mmHg (p = .026), 6MWD <370 m (p = 0.008), resting SpO(2) <92 % (p = 0.02) and peak-walk SpO(2) <87 % (p = 0.012). CONCLUSION: PH-target vasodilator therapy improved NYHA functional class and 6MWD up to one year in highly selected patients with severe PH-COPD. Poor exercise capacity, low SpO(2) and high mean pulmonary artery pressure at baseline but not airflow obstruction were associated with unfavourable outcome.

Effect of oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary pulmonary hypertension and sleep-disturbed breathing.

BACKGROUND: Sleep-disturbed breathing (SDB) is common in patients with precapillary pulmonary hypertension (PH). Nocturnal oxygen therapy (NOT) and acetazolamide improve SDB in patients with PH, and NOT improves exercise capacity. We investigated the effect of NOT and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in patients with PH and SDB. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 23 patients with arterial (n = 16) or chronic thromboembolic PH (n = 7) and SDB defined as a mean nocturnal oxygen saturation < 90% or dips (> 3%) > 10/h with daytime Pao2 ≥ 7.3 kPa were studied. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo each during 1 week separated by a 1-week washout period. Three-lead ECG was recorded during overnight polysomnography at the end of each treatment period. Repolarization indices were averaged over three cardiac cycles at late evening and at early morning, and nocturnal arrhythmias were counted. RESULTS: NOT was associated with a lower overnight (68 ± 10 beats/min vs 72 ± 9 beats/min, P = .010) and early morning heart rate compared with placebo. At late evening, the heart rate-adjusted PQ time was increased under acetazolamide compared with placebo (mean difference, 10 milliseconds; 95% CI, 0-20 milliseconds; P = .042). In the morning under NOT, the heart rate-adjusted QT (QTc) interval was decreased compared with placebo (mean difference, -25 milliseconds; 95% CI, -45 to -6 milliseconds; P = .007), and the interval between the peak and the end of the T wave on the ECG was shorter compared with acetazolamide (mean difference, -11 milliseconds; 95% CI, -21 to -1 milliseconds; P = .028). Arrhythmias were rare and similar with all treatments. CONCLUSIONS: In patients with PH with SDB, NOT reduces nocturnal heart rate and QTc in the morning, thus, favorably modifying prognostic markers. TRIAL REGISTRY: ClinicalTrials.gov; No.: NTC-01427192; URL: www.clinicaltrials.gov.

Tobacco smoke exposure in pulmonary arterial and thromboembolic pulmonary hypertension.

BACKGROUND: Animal studies and data from a single-center study suggest that tobacco smoke exposure may be a risk factor for precapillary pulmonary hypertension (PH). OBJECTIVE: We aimed to survey tobacco smoke exposure in a large PH collective and to compare it with epidemiological data from healthy subjects. METHODS: This is an international, multicenter, case-control study including patients with pulmonary arterial and chronic thromboembolic PH. All patients were asked specific questions about tobacco smoke exposure. Healthy controls were retrieved from the Swiss Health Survey (n = 18,747). RESULTS: Overall (n = 472), 49% of PH patients were smokers and there was a clear sex difference (women 37%, men 71%). Significantly more PH men were smokers compared with healthy controls, whereas less PH women were ever active smokers. However, 50% of the non-smoking PH women were exposed to secondhand smoke, leading to a significantly higher number of tobacco smoke-exposed individuals compared to healthy controls. PH smokers were significantly younger compared to those not exposed. CONCLUSION: Active and environmental tobacco smoke exposure is common in PH. The higher prevalence of male PH smokers, the higher exposure to environmental tobacco smoke in PH women compared to healthy controls and the lower age at PH diagnosis in smokers may indicate a pathogenic role of tobacco smoke exposure in PH.

Inflammatory cytokines in pulmonary hypertension.

Pulmonary hypertension is an "umbrella term" used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.