| 1. |
- Kjellström, Barbro, et al.
(author)
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Sex-specific differences and survival in patients with idiopathic pulmonary arterial hypertension 2008-2016
- 2019
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In: ERJ Open Research. - Lausanne, Switzerland : European Respiratory Society (ERS). - 2312-0541. ; 5:3
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Journal article (peer-reviewed)abstract
- Background: Women with idiopathic pulmonary arterial hypertension (IPAH) have been found to have a worse haemodynamic status at diagnosis, but better survival than men. Over the past decade, demographics have changed and new treatments have become available. The objective of this study was to investigate sex differences in an incident IPAH population diagnosed between 2008 and 2016.Methods: Differences in clinical characteristics of patients included in the Swedish Pulmonary Arterial Hypertension Register (SPAHR) were analysed at the time of diagnosis. Survival by sex was investigated using Cox proportional hazard regression and Kaplan-Meier curves.Results: The study included 271 patients diagnosed with IPAH, median age was 68 (1st-3rd quartiles 54-74) years and 56% were women. At diagnosis, women were younger, had lower pulmonary vascular resistance and fewer comorbidities and more often received a combination of PAH-targeted therapies than men. Men had worse survival rates than women (hazard ratio 1.49; CI 1.02-2.18; p=0.038), but this difference did not remain after adjustment for age (hazard ratio 1.30; CI 0.89-1.90; p=0.178).Conclusions: Men with incident IPAH have worse crude survival than women. This is due to women being younger with a less pronounced comorbidity burden than men at the time of diagnosis.
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| 2. |
- Celik, Selvi, et al.
(author)
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Extracellular Vesicle-Associated TWEAK Contributes to Vascular Inflammation and Remodeling During Acute Cellular Rejection
- 2023
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In: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 8:5, s. 439-456
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Journal article (peer-reviewed)abstract
- Acute cellular rejection (ACR) is a leading cause of graft loss and death after heart transplantation despite effective immunosuppressive therapies. The identification of factors that impair graft vascular barrier function or promote immune cell recruitment during ACR could provide new therapeutic opportunities for the treatment of patients who receive transplants. In 2 ACR cohorts, we found the extracellular vesicle-associated cytokine TWEAK to be elevated during ACR. Vesicular TWEAK promoted expression of proinflammatory genes and the release of chemoattractant cytokines from human cardiac endothelial cells. We conclude that vesicular TWEAK is a novel target with potential therapeutic implications in ACR.
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| 3. |
- Andreassen, A. K., et al.
(author)
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Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study
- 2016
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In: American Journal of Transplantation. - : WILEY-BLACKWELL. - 1600-6135 .- 1600-6143. ; 16:4, s. 1238-1247
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Journal article (peer-reviewed)abstract
- In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4mL/min (standard deviation [SD] 20.2mL/min) versus 59.2mL/min (SD 17.4mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3mL/min (95% CI 11.1-25.6mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade 2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p=0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage. A follow-up study of the SCHEDULE trial, which randomized de novo heart transplant recipients to everolimus with cyclosporine discontinuation or to standard-exposure cyclosporine, shows that measured glomerular filtration rate remains significantly higher in the everolimus group at three years posttransplant, with significantly reduced progression of allograft vasculopathy compared to cyclosporine therapy.
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| 4. |
- Gullestad, Lars, et al.
(author)
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Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial
- 2016
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In: Transplant International. - : Wiley-Blackwell Publishing Inc.. - 0934-0874 .- 1432-2277. ; 29:7, s. 819-829
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Journal article (peer-reviewed)abstract
- The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)ml/min with everolimus versus -7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.
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| 5. |
- Jansson, Kjell, et al.
(author)
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Pulmonell arteriell hypertension : allvarlig prognos trots stora framsteg
- 2015
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In: Läkartidningen. - : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 112:44-45, s. 1972-1976
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Journal article (peer-reviewed)abstract
- Pulmonell arteriell hypertension är en allvarlig sjukdom där förbättrad diagnostik och förfinad behandling bidragit till att förbättra patienternas prognos och funktionsförmåga. Svensk förening för pulmonell hypertension (SveFPH) arbetar för en nationell samsyn, kvalitetsregister och multiprofessionellt omhändertagande. Patienter med pulmonell arteriell hypertension är vanligare än man tidigare uppfattat och medelåldern ligger högre än förväntat, men i nivå med andra internationella register. Drygt 40 procent av patienterna behandlas med fler än ett för pulmonell arteriell hypertension specifikt läkemedel, vilket förväntas öka och initieras redan i ett tidigt skede.
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| 6. |
- Lundgren, Jakob, et al.
(author)
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Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation
- 2018
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In: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 52:4, s. 196-204
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters.DESIGN: 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation.RESULTS: In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT.CONCLUSIONS: Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered "normal" after HT.
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| 7. |
- Rådegran, Göran, et al.
(author)
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Characteristics and survival of adult Swedish PAH and CTEPH patients 2000-2014
- 2016
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In: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 50:4, s. 243-250
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The Swedish Pulmonary Arterial Hypertension Register (SPAHR) is an open continuous register, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients from 2000 and onwards. We hereby launch the first data from SPAHR, defining baseline characteristics and survival of Swedish PAH and CTEPH patients.DESIGN: Incident PAH and CTEPH patients 2008-2014 from all seven Swedish PAH-centres were specifically reviewed.RESULTS: There were 457 PAH (median age: 67 years, 64% female) and 183 CTEPH (median age: 70 years, 50% female) patients, whereof 77 and 81%, respectively, were in functional class III-IV at diagnosis. Systemic hypertension, diabetes, ischaemic heart disease and atrial fibrillation were common comorbidities, particularly in those >65 years. One-, 3- and 5-year survival was 85%, 71% and 59% for PAH patients. Corresponding numbers for CTEPH patients with versus without pulmonary endarterectomy were 96%, 89% and 86% versus 91%, 75% and 69%, respectively. In 2014, the incidence of IPAH/HPAH, associated PAH and CTEPH was 5, 3 and 2 per million inhabitants and year, and the prevalence was 25, 24 and 19 per million inhabitants.CONCLUSION: The majority of the PAH and CTEPH patients were diagnosed at age >65 years, in functional class III-IV, and exhibiting several comorbidities. PAH survival in SPAHR was similar to other registers.
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| 8. |
- Sandqvist, Anna, et al.
(author)
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Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction
- 2018
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In: Heart and Vessels. - : Springer. - 0910-8327 .- 1615-2573. ; 33:3, s. 255-263
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Journal article (peer-reviewed)abstract
- Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (r s = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (r s = −0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.
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| 9. |
- Sandqvist, Anna, 1980-, et al.
(author)
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Differences in plasma L-arginine and dimethylarginines in diagnosis and treatment of pulmonary arterial hypertension: a prospective observational study
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Other publication (other academic/artistic)abstract
- Introduction Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance in vasoactive substances and remodelling of pulmonary vasculature. Asymmetric dimethylarginine (ADMA) inhibits the enzyme nitric oxide synthase, which generates nitric oxide (NO), a molecule causing smooth muscle cell relaxation. Our aim was to investigate the plasma concentrations of ADMA, symmetrical dimethylarginine (SDMA), L-arginine, L-ornithine and L- citrulline at diagnosis and during PAH-specific treatment in patients with PAH compared to patients with left heart failure (LVHF) and healthy subjects.Methods This is an observational, prospective multicentre study of 21 PAH patients. For comparison 14 patients with LVHF and 27 healthy subjects were investigated. Blood samples were collected and ADMA, SDMA, L-arginine, L-ornithine and L-citrulline were analysed with liquid chromatography – tandem mass spectrometry (LC-MS/MS).Results Baseline plasma concentrations of ADMA and SDMA were higher whereas the L-arginine concentrations and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p<0.001). Patients with PAH had lower L-arginine concentration than patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to L-arginine and L- arginine/ADMA in PAH at baseline (p<0.05). At follow-up, patients on mono- or combination therapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on phosphodiesterase type-5 inhibitors (PDE5-inhibitors) had higher ADMA levels compared to patients without PDE5-inhibitor treatment (p<0.05).Conclusion Concentrations of L-arginine were decreased and dimethylarginines were increased in PAH compared to healthy subjects. L-arginine was decreased in PAH compared to LVHF. L- arginine/ADMA ratio correlated to WHO functional class and L-arginine and L-arginine/ADMA ratio correlated to 6MWD. PAH-specific treatment influences the levels of L-arginine and dimethylarginines.
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| 10. |
- 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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