| 11. |
- Bouzina, Habib, et al.
(author)
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Higher plasma fibroblast growth factor 23 levels are associated with a higher risk profile in pulmonary arterial hypertension
- 2019
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In: Pulmonary Circulation. - : Wiley. - 2045-8932 .- 2045-8940. ; 9:4
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Journal article (peer-reviewed)abstract
- Metabolic abnormalities are proposed to contribute to pulmonary arterial as well as right ventricular remodelling in pulmonary arterial hypertension. Among the proposed abnormalities are altered glucose and lipid processing, mitochondrial malfunction, oxidative stress as well as vitamin D and iron abnormalities. In the present study, we investigated 11 metabolic plasma biomarkers, with the hypothesis that metabolic proteins may mirror disease severity in pulmonary arterial hypertension. Using proximity extension assays, plasma metabolic biomarkers were measured in 48 pulmonary arterial hypertension patients at diagnosis and, in 33 of them, at an early treatment follow-up, as well as in 16 healthy controls. Among the studied metabolic biomarkers, plasma fibroblast growth factor-23 (p < 0.001), fibroblast growth factor-21 (p < 0.001), fatty acid binding protein 4 (p < 0.001) and lectin-like oxidised low-density lipoprotein receptor 1 (p < 0.001) were increased and paraoxonase-3 was decreased (p < 0.001) in pulmonary arterial hypertension at diagnosis versus controls. Fibroblast growth factor-23 showed the strongest correlations to studied clinical parameters and was therefore selected for further analyses. Fibroblast growth factor-23 correlated specifically to mean right atrial pressure (r = 0.67, p < 0.001), six-min walking distance (r = −0.66, p < 0.001), NT-proBNP (r = 0.64, p < 0.001), venous oxygen saturation (r = −0.61, p < 0.001), cardiac index (r = −0.39, p < 0.007) and pulmonary vascular resistance (r = 0.37, p < 0.01). Fibroblast growth factor-23 correlated moreover to ESC/ERS (r = 0.72, p < 0.001) and the REVEAL risk score (r = 0.61, p < 0.001). Comparing early treatment follow-up with baseline, fibroblast growth factor-23 decreased (p < 0.02), with changes in fibroblast growth factor-23 correlating to changes in six-min walking distance (r = −0.56, p < 0.003), venous oxygen saturation (r = −0.46, p < 0.01), pulmonary vascular resistance (r = 0.43, p < 0.02), mean right atrial pressure (r = 0.38, p < 0.04) and cardiac index (r = −0.39, p < 0.04). Elevated plasma fibroblast growth factor-23 levels at pulmonary arterial hypertension diagnosis were associated with worse haemodynamics and a higher risk profile, and were decreased after the administration of pulmonary arterial hypertension-specific treatment.
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| 12. |
- Bouzina, Habib, et al.
(author)
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Low plasma stem cell factor combined with high transforming growth factor-α identifies high-risk patients in pulmonary arterial hypertension
- 2018
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In: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 4:4
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Journal article (peer-reviewed)abstract
- In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk. Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines. Plasma SCF was decreased (p=0.013) and TGF-α was increased (p<0.0001) in PAH patients compared to controls. SCF correlated to pulmonary vascular resistance (r=-0.66, p<0.0001), cardiac index (r=0.66, p<0.0001), venous oxygen saturation (r=0.47, p<0.0008), mean right atrial pressure (r=-0.44, p<0.002) and N-terminal pro-brain natriuretic protein (r=-0.39, p<0.006). SCF was lower in "high-risk" compared to "intermediate-risk" (p=0.0015) or "low-risk" (p=0.0009) PAH patients. SCF and TGF-α levels combined (SCF/TGF-α) resulted in 85.7% sensitivity and 81.5% specificity for detecting high-risk patients (p<0.0001). Finally, REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) risk scores in PAH patients correlated to SCF/TGF-α levels (r=-0.50, p=0.0003). In conclusion, low plasma SCF combined with high TGF-α identifies high-risk PAH patients at baseline. Lower circulating SCF levels, which are associated with worse haemodynamics, may be related to the c-Kit accumulation previously observed in PAH.
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| 13. |
- Bredfelt, Anna, et al.
(author)
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Increased right atrial volume measured with cardiac magnetic resonance is associated with worse clinical outcome in patients with pre-capillary pulmonary hypertension
- 2018
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In: ESC Heart Failure. - : Wiley. - 2055-5822. ; 5:5, s. 864-875
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Journal article (peer-reviewed)abstract
- Aims: Pre-capillary pulmonary hypertension (PHpre-cap) has a poor prognosis, especially when caused by pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). Whether cardiac magnetic resonance (CMR)-based quantification of atrial volumes in PHpre-cap is beneficial in risk assessment is unknown. The aims were to investigate if (i) atrial volumes using CMR are associated with death or lung transplantation in PHpre-cap, (ii) atrial volumes differ among four unmatched major PHpre-cap subgroups, and (iii) atrial volumes differ between SSc-PAH and idiopathic/familial PAH (IPAH/FPAH) when matched for pulmonary vascular resistance (PVR). Methods and results: Seventy-five PHpre-cap patients (57 ± 19 years, 53 female, 43 de novo) with CMR and right heart catheterization were retrospectively included. Short-axis stacks of cine images were analysed, and right and left atrial maximum (RAVmax and LAVmax) and minimum volume (RAVmin and LAVmin) were indexed for body surface area. Increased (mean + 2 SD) and reduced (mean – 2 SD) volumes were predefined from CMR normal values. Transplantation-free survival was lower in patients with increased RAVmax than in those with normal [hazard ratio (HR) = 2.1, 95% confidence interval (CI) 1.1–4.0] but did not differ between those with reduced LAVmax and normal (HR 2.0, 95% CI 0.8–5.1). RAVmax and RAVmin showed no differences among unmatched or matched groups (P = ns). When matched for PVR, LAVmax, LAVmin, and pulmonary artery wedge pressure were reduced in SSc-PAH compared with IPAH/FPAH (95% CI 0.3–21.4, 95% CI 0.8–19.6, and 95% CI 2–7, respectively). Conclusions: Patients with PHpre-cap and increased right atrial volume measured with CMR had worse clinical outcome. When matched for PVR, left atrial volume was lower in SSc-PAH than in IPAH/FPAH, consistent with left-sided underfilling, indicating a potential differentiator between the groups.
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| 14. |
- Celik, Selvi, et al.
(author)
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Functional Screening Identifies MicroRNA Regulators of Corin Activity and Atrial Natriuretic Peptide Biogenesis
- 2019
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In: Molecular and Cellular Biology. - 0270-7306. ; 39:23
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Journal article (peer-reviewed)abstract
- Atrial natriuretic peptide (ANP) represents an attractive therapeutic target in hypertension and heart failure. The biologically active form of ANP is produced by the cardiac serine protease corin, and modulation of its activity might therefore represent a novel approach for ANP augmentation. MicroRNAs (miRNAs) are pervasive regulators of gene expression, but their potential role in regulating corin activity has not been elucidated. Our aim was to systematically identify and characterize miRNA regulators of corin activity in human cardiomyocytes. An assay for measuring serine protease activity in human induced pluripotent stem cell (iPS)-derived cardiomyocytes was used to perform a comprehensive screening of miRNA family inhibitors (n = 42). miRNA 1-3p (miR-1-3p) was identified as a potent inhibitor of corin activity. The interaction between miR-1-3p and a specific target site in the CORIN 3' untranslated region (3' UTR) was confirmed through argonaute 2 (AGO2)-RNA immunoprecipitation and reporter assays. Inhibition of miR-1-3p resulted in upregulation of CORIN gene and protein expression, as well as a concomitant increase in extracellular ANP. Additionally, miR-1-3p was found to interact with and inhibit the expression of several transcriptional activators of ANP gene expression. In conclusion, we have identified a novel regulator of corin activity and ANP biogenesis in human cardiomyocytes that might be of potential future therapeutic utility.
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| 15. |
- Egerstedt, Anna, et al.
(author)
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Profiling of the plasma proteome across different stages of human heart failure
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 5830-
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Journal article (peer-reviewed)abstract
- Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.
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| 16. |
- González Henríquez, J J, et al.
(author)
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A new equation to estimate temperature-corrected PaCO2 from PET CO2 during exercise in normoxia and hypoxia.
- 2015
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In: Scandinavian Journal of Medicine & Science in Sports. - : Wiley. - 1600-0838 .- 0905-7188. ; 26:9, s. 1045-1051
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Journal article (peer-reviewed)abstract
- End-tidal PCO2 (PET CO2 ) has been used to estimate arterial pressure CO2 (Pa CO2 ). However, the influence of blood temperature on the Pa CO2 has not been taken into account. Moreover, there is no equation validated to predict Pa CO2 during exercise in severe acute hypoxia. To develop a new equation to predict temperature-corrected Pa CO2 values during exercise in normoxia and severe acute hypoxia, 11 volunteers (21.2 ± 2.1 years) performed incremental exercise to exhaustion in normoxia (Nox, PI O2 : 143 mmHg) and hypoxia (Hyp, PI O2 : 73 mmHg), while arterial blood gases and temperature (ABT) were simultaneously measured together with end-tidal PCO2 (PET CO2 ). The Jones et al. equation tended to underestimate the temperature corrected (tc) Pa CO2 during exercise in hypoxia, with greater deviation the lower the Pa CO2 tc (r = 0.39, P < 0.05). The new equation has been developed using a random-effects regression analysis model, which allows predicting Pa CO2 tc both in normoxia and hypoxia: Pa CO2 tc = 8.607 + 0.716 × PET CO2 [R(2) = 0.91; intercept SE = 1.022 (P < 0.001) and slope SE = 0.027 (P < 0.001)]. This equation may prove useful in noninvasive studies of brain hemodynamics, where an accurate estimation of Pa CO2 is needed to calculate the end-tidal-to-arterial PCO2 difference, which can be used as an index of pulmonary gas exchange efficiency.
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| 17. |
- Hjalmarsson, Clara, 1969, et al.
(author)
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Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension
- 2018
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In: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 51:5
-
Journal article (peer-reviewed)abstract
- Recent reports from worldwide pulmonary hypertension registries show a new demographic picture for patients with idiopathic pulmonary arterial hypertension (IPAH), with an increasing prevalence among the elderly. We aimed to investigate the effects of age and comorbidity on risk stratification and outcome of patients with incident IPAH. The study population (n=264) was categorised into four age groups: 18-45, 46-64, 65-74 and 75 years. Individual risk profiles were determined according to a risk assessment instrument, based on the European Society of Cardiology and the European Respiratory Society guidelines. The change in risk group from baseline to follow-up (median 5 months) and survival were compared across age groups. In the two youngest age groups, a significant number of patients improved (18-45 years, Z= −4.613, p<0.001; 46-64 years, Z= −2.125, p=0.034), but no significant improvement was found in the older patient groups. 5-year survival was highest in patients aged 18-45 years (88%), while the survival rates were 63%, 56% and 36% for patients in the groups 46-64, 65-74 and 75 years, respectively (p<0.001). Ischaemic heart disease and kidney dysfunction independently predicted survival. These findings highlight the importance of age and specific comorbidities as prognostic markers of outcome in addition to established risk assessment algorithms.
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| 18. |
- Ingvarsson, Annika, et al.
(author)
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Impact of gender on echocardiographic characteristics in heart transplant recipients
- 2019
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In: Clinical Physiology and Functional Imaging. - : Wiley. - 1475-0961 .- 1475-097X. ; 39:4, s. 246-254
-
Journal article (peer-reviewed)abstract
- Aims: Assessment following heart transplantation (HTx) is routinely performed using transthoracic echocardiography. Differences in long-term mortality following HTx related to donor-recipient matching have been reported, but effects of gender on cardiac size and function are not well studied. The aims of this study were to evaluate differences in echocardiographic characteristics of HTx recipients defined by gender. Methods and results: The study prospectively enrolled 123 (n = 34 female) HTx recipients of which 23 recipients was donor-recipient gender mismatched. Patients were examined with 2-dimensional echocardiography using Philips iE33 ultrasound system. Data were analysed across strata based on recipient gender and gender mismatch. Male recipients had larger left ventricular (LV) mass, thicker septal wall (P<0·001) and larger absolute LV volumes (P<0·001). Mean LV ejection fraction (EF) was higher in females (P<0·05), but no differences in conventional parameters of right ventricular (RV) function were found. Ventricular strain was higher in females than in males: LV global longitudinal strain (P<0·01), RV global longitudinal strain (P<0·05) and RV lateral free wall (P<0·05). The male group receiving a female donor heart had comparable EF and strain parameters to the female group receiving a gender-matched heart. Conclusion: We found that female recipient gender was associated with smaller chamber size, higher LV EF and better LV and RV longitudinal strain. Gender-mismatched male recipients appeared to exhibit function parameters similar to gender-matched female recipients. Our results indicate that the gender aspect, analogous to current reference guidelines in general population, should be taken into consideration when examining patients post-HTx.
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| 19. |
- Ingvarsson, Annika, et al.
(author)
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Normal Reference Ranges for Transthoracic Echocardiography Following Heart Transplantation
- 2018
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In: Journal of the American Society of Echocardiography. - : Elsevier BV. - 0894-7317. ; 31:3, s. 349-360
-
Journal article (peer-reviewed)abstract
- Background: Heart function following heart transplantation (HTx) is influenced by numerous factors. It is typically evaluated using transthoracic echocardiography, but reference values are currently unavailable for this context. The primary aim of the present study was to derive echocardiographic reference values for chamber size and function, including cardiac mechanics, in clinically stable HTx patients. Methods: The study enrolled 124 healthy HTx patients examined prospectively. Patients underwent comprehensive two-dimensional echocardiographic examinations according to contemporary guidelines. Results were compared with recognized reference values for healthy subjects. Results: Compared with guidelines, larger atrial dimensions were seen in HTx patients. Left ventricular (LV) diastolic volume was smaller, and LV wall thickness was increased. With respect to LV function, both ejection fraction (62 ± 7%, P < .01) and global longitudinal strain (-16.5 ± 3.3%, P < .0001) were lower. All measures of right ventricular (RV) size were greater than reference values (P < .0001), and all measures of RV function were reduced (tricuspid annular plane systolic excursion 15 ± 4 mm [. P < .0001], RV systolic tissue Doppler velocity 10 ± 6 cm/sec [. P < .0001], fractional area change 40 ± 8% [. P < .0001], and RV free wall strain -16.9 ± 4.2% [. P < .0001]). Ejection fraction and LV global longitudinal strain were significantly lower in patients with previous rejection. Conclusion: The findings of this study indicate that the distribution of routinely used echocardiographic measures differs between stable HTx patients and healthy subjects. In particular, markedly larger RV and atrial volumes and mild reductions in both LV and RV longitudinal strain were evident. The observed differences could be clinically relevant in the assessment of HTx patients, and specific reference values should be applied in this context.
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| 20. |
- Ivarsson, Bodil, et al.
(author)
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Adherence and medication belief in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension : A nationwide population-based cohort survey
- 2018
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In: Clinical Respiratory Journal. - : Wiley. - 1752-6981 .- 1752-699X. ; 12:6, s. 2029-2035
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Journal article (peer-reviewed)abstract
- Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare diseases with a gradual decline in physical health. Adherence to treatment is crucial in these very symptomatic and life threatening diseases. Objective: To describe PAH and CTEPH patients experience of their self-reported medication adherence, beliefs about medicines and information about treatment. Methods: A quantitative, descriptive, national cohort survey that included adult patients from all PAH-centres in Sweden. All patients received questionnaires by mail: The Morisky Medication Adherence Scale (MMAS-8) assesses treatment-related attitudes and behaviour problems, the Beliefs about Medicines Questionnaire-Specific scale (BMQ-S) assesses the patient's perception of drug intake and the QLQ-INFO25 multi-item scale about medical treatment information. Results: The response rate was 74% (n = 325), mean age 66 ± 14 years, 58% were female and 69% were diagnosed with PAH and 31% with CTEPH. Time from diagnosis was 4.7 ± 4.2 years. More than half of the patients (57%) reported a high level of adherence. There was no difference in the patients' beliefs of the necessity of the medications to control their illness when comparing those with high, medium or low adherence. Despite high satisfaction with the information, concerns about potential adverse effects of taking the medication were significantly related to adherence. Conclusions: Treatment adherence is relatively high but still needs improvement. The multi-disciplinary PAH team should, together with the patient, seek strategies to improve adherence and prevent concern.
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