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Background: Despite optimized medical therapy, severe idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease with a poor outcome. Autoantibodies have been detected in IPAH that can contribute to worsening of the disease. Objectives: The objective of this prospective, open-label, single-arm, multicenter trial was to evaluate the safety and efficacy of immunoadsorption (IA) as an add-on to optimized medical treatment for patients with IPAH. Methods: A total of 10 IPAH patients received IA over 5 days. Their clinical parameters, including hemodynamics measured by right heart catheter, were assessed at baseline and after 3 and 6 months. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included the change in 6-min walking distance, quality of life, safety, and plasma levels of IgG and autoantibodies. Results: The evaluation of the 10 IPAH patients (75% female; 51 ± 12 years; 166 ± 10 cm; WHO functional class III; 53% on combination therapy) revealed that IA was a safe procedure that efficiently removed IgG and autoantibodies from the circulation. After 3 months, the mean PVR improved significantly by 13.2% (p = 0.03) and the cardiac index improved by 13.1%, but no significant changes were found in 6-min walking distance. The quality of life physical functioning subscale score significantly improved after 6 months. The serious adverse events in 3 patients were possibly related to IA and included pneumonia, temporary disturbance in attention, and thrombocytopenia. Conclusions: IA as an add-on to targeted medical treatment for IPAH is a safe procedure with beneficial effects on hemodynamics, especially in patients with high levels of autoantibodies. Larger-scale controlled studies are needed to assess its efficacy in IPAH and to identify responders.
Riociguat is one of several approved therapies available for patients with pulmonary arterial hypertension (PAH). Treatment should be initiated and monitored at an expert center by a physician experienced in treating PAH, and the dose adjusted in the absence of signs and symptoms of hypotension. In certain populations, including patients with hepatic or renal impairment, the elderly, and smokers, riociguat exposure may differ, and dose adjustments should therefore be made with caution according to the established scheme. Common adverse events are often easily managed, particularly if they are discussed before starting therapy. Combination therapy with riociguat and other PAH-targeted agents is feasible and generally well tolerated, although the coadministration of phosphodiesterase type 5 inhibitors (PDE5i) and riociguat is contraindicated. An open-label, randomized study is currently ongoing to assess whether patients who do not achieve treatment goals while receiving PDE5i may benefit from switching to riociguat. In this review, we provide a clinical view on the practical management of patients with PAH receiving riociguat, with a focus on the opinions and personal experience of the authors.
The reviews of this paper are available via the supplemental material section.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often
caused by recurrent emboli. These are also frequently found in patients with myeloproliferative
diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition
to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes
and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening
was conducted for pathogenic variants using a gene panel based on next generation sequencing.
CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients
4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*)
in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant,
c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative
disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected
(p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought.
The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH
development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be
considered also for CTEPH patients.
Studies comparing thermodilution (TD) and the direct Fick method (dFM) for cardiac output (CO) measurement are rare. We compared CO measurements between TD (2–5 cold water injections), the dFM, and indirect Fick method (iFM) at rest and during exercise, and assessed the effect of averaging different numbers of TD measurements during exercise. This retrospective study included 300 patients (52.3% women, mean age 66 ± 11 years) having pulmonary hypertension (76.0%) or unexplained dyspnea. Invasive hemodynamic and gas exchange parameters were measured at rest (supine; n = 300) and during unloaded cycling (semi-supine; n = 275) and 25-W exercise (semi-supine; n = 240). All three methods showed significant differences in CO measurement (ΔCO) at rest (p ≤ 0.001; ΔCO > 1 L/min: 45.0% [iFM vs. dFM], 42.0% [iFM vs. TD], and 45.7% [TD vs. dFM]). ΔCO (TD vs. dFM) was significant during unloaded cycling (p < 0.001; ΔCO > 1 L/min: 56.6%) but not during 25-W exercise (p = 0.137; ΔCO > 1 L/min: 52.8%). ΔCO (TD vs. dFM) during 25-W exercise was significant when using one or two (p ≤ 0.01) but not three (p = 0.06) TD measurements. Mean ΔCO (TD [≥3 measurements] vs. dFM) was −0.43 ± 1.98 and −0.06 ± 2.29 L/min during unloaded and 25-W exercise, respectively. Thus, TD and dFM CO measurements are comparable during 25-W exercise (averaging ≥3 TD measurements), but not during unloaded cycling or at rest. Individual ΔCOs vary substantially and require critical interpretation to avoid CO misclassification.
The establishment of a guideline for long-term noninvasive ventilation treatment (LTH-NIV) of acute hypercapnic exacerbations of chronic obstructive pulmonary disease (AECOPD) requiring acute ventilation has proven elusive. Most studies thus far have shown no mortality benefit of long-term noninvasive ventilation treatment. Using retrospective analysis of the data of our patients (n = 143) recruited from 2012 to 2019, we aimed to compare patients discharged with and without long-term noninvasive ventilation. The follow-up results showed no significant difference (p = 0.233) between the groups [LTH-NIV (n = 83); non-NIV (n = 60)] regarding readmission due to clinical worsening. However, the first- and second-year survival rates were 82% and 72%, respectively, in the LTH-NIV group and significantly different (p = 0.023) from 67 and 55% in the non-NIV group. The statistical models showed a significant mortality risk for the non-NIV group, with a hazard ratio (HR) of 2.82 (1.31; 6.03). To the best of our knowledge, this is the first study to demonstrate the mortality benefit of long-term NIV therapy for patients with AECOPD under real-world conditions.
Background
Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome.
Case presentation
The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally.
Conclusion
CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.
Background: Invasive cardiopulmonary exercise testing (iCPET) is an integral part in the advanced diagnostic workup of pulmonary hypertension (PH). Our study evaluated the relation between hemodynamic and respiratory parameters at two different resting conditions and two defined low exercise levels with a close synchronization of measurements in a broad variety of dyspnea patients. Subjects and methods: We included 146 patients (median age 69 years, range 22 to 85 years, n = 72 female) with dyspnea of uncertain origin. Invasive hemodynamic and gas exchange parameters were measured at rest, 45° upright position, unloaded cycling, 25 and 50 W exercise. All measurements were performed in a single RHC procedure. Results: Oxygen uptake (VO2/body mass) correlated significantly with cardiac index (all p ≤ 0.002) at every resting and exercise level and with every method of cardiac output measurement (thermodilution, method of Fick). Mean pulmonary arterial pressure (PAPmean) correlated with all respiratory parameters (respiratory rate, partial end-tidal pressures of oxygen and carbon dioxide [petCO2 and petO2], ventilation/carbon dioxide resp. oxygen ratio [VE/VCO2, VE/VO2], and minute ventilation [VE], all p < 0.05). These correlations improved with increasing exercise levels from rest via unloaded cycling to 25 W. There was no correlation with right atrial or pulmonary arterial wedge pressure. Summary: In dyspnea patients of different etiologies, the cardiac index is closely linked to VO2 at every level of rest and submaximal exercise. PAPmean is the only pressure that correlates with different respiratory parameters, but this correlation is highly significant and stable at rest, unloaded cycling and at 25 W.
Objective: Menopause is associated with multiple health risks. In several studies, a higher incidence or a higher risk for obstructive sleep apnea (OSA) in post-menopausal than pre-menopausal women is reported. This study was designed to verify such a connection between menopause and OSA in a population-based sample.
Methods: For a subsample (N = 1209) of the Study of Health in Pomerania (N = 4420), complete polysomnography data was available. Of these, 559 females completed a structured interview about their menstrual cycle. Splines and ordinal regression analysis were used to analyze the resulting data.
Results: In the ordinal regression analysis, a significant association between the apnea–hypopnea index (AHI) and menopause indicated that post-menopausal women had a substantially higher risk of OSA. In accordance with previous studies, risk indicators such as body mass index (BMI), age, and the influence of hysterectomies or total oophorectomies were included in the model.
Conclusions: Our results clearly confirmed the assumed connection between menopause and OSA. This is important because OSA is most often associated with male patients, and it warrants further research into the underlying mechanisms.
Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer’s disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50–81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.