| 1. |
- Ahn, J. M., et al.
(författare)
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Microcirculatory Resistance Predicts Allograft Rejection and Cardiac Events After Heart Transplantation
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 78:24, s. 2425-2435
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Single-center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute rejection. OBJECTIVES: The goal of this study was to validate whether IMR measured early after transplantation can predict subsequent acute rejection and long-term outcome in a large multicenter cohort. METHODS: From 5 international cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was acute allograft rejection (AAR) within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE) (the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission) at 10 years. RESULTS: IMR was measured at a median of 7 weeks (interquartile range: 3-10 weeks) post-transplantation. At 1 year, the incidence of AAR was 14.4%. IMR was associated proportionally with the risk of AAR (per increase of 1-U IMR; adjusted hazard ratio [aHR]: 1.04; 95% confidence interval [CI]: 1.02-1.06; p < 0.001). The incidence of AAR in patients with an IMR >= 18 was 23.8%, whereas the incidence of AAR in those with an IMR <18 was 6.3% (aHR: 3.93; 95% CI: 1.77-8.73; P = 0.001). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-U IMR; aHR: 1.02; 95% CI: 1.01-1.04; P = 0.005). CONCLUSIONS: IMR measured early after heart transplantation is associated with subsequent AAR at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized posttransplantation management. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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| 2. |
- Andreassen, A. K., et al.
(författare)
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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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Ingår i: American Journal of Transplantation. - : WILEY-BLACKWELL. - 1600-6135 .- 1600-6143. ; 16:4, s. 1238-1247
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Karason, Kristjan, 1962, et al.
(författare)
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Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial
- 2020
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:2, s. 739-50
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Tidskriftsartikel (refereegranskat)abstract
- Aims Patients with advanced heart failure (AdHF) who are ineligible for heart transplantation (HTx) can become candidates for treatment with a left ventricular assist device (LVAD) in some countries, but not others. This reflects the lack of a systematic analysis of the usefulness of LVAD systems in this context, and of their benefits, limitations and cost-effectiveness. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) study is a Phase IV, prospective, 1:1 randomized, non-blinded, multicentre trial that will examine the impact of assignment to mechanical circulatory support with guideline-directed LVAD destination therapy (GD-LVAD-DT) using the HeartMate 3 (HM3) continuous flow pump vs. guideline-directed medical therapy (GDMT) on survival in a population of AdHF patients ineligible for HTx. Methods A total of 80 patients will be recruited to SweVAD at the seven university hospitals in Sweden. The study population will comprise patients with AdHF (New York Heart Association class IIIB-IV, INTERMACS profile 2-6) who display signs of poor prognosis despite GDMT and who are not considered eligible for HTx. Participants will be followed for 2 years or until death occurs. Other endpoints will be determined by blinded adjudication. Patients who remain on study-assigned interventions beyond 2 years will be asked to continue follow-up for outcomes and adverse events for up to 5 years. Conclusion The SweVAD study will compare survival, medium-term benefits, costs and potential hazards between GD-LVAD-DT and GDMT and will provide a valuable reference point to guide destination therapy strategies for patients with AdHF ineligible for HTx.
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| 4. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:8, s. 2406-2420
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Tidskriftsartikel (refereegranskat)abstract
- The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy
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| 5. |
- Ahn, Jung-Min, et al.
(författare)
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Prognostic value of comprehensive intracoronary physiology assessment early after heart transplantation.
- 2021
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 42:48, s. 4918-4929
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the long-term prognostic value of invasively assessing coronary physiology after heart transplantation in a large multicentre registry.Comprehensive intracoronary physiology assessment measuring fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) was performed in 254 patients at baseline (a median of 7.2weeks) and in 240 patients at 1year after transplantation (199 patients had both baseline and 1-year measurement). Patients were classified into those with normal physiology, reduced FFR (FFR≤0.80), and microvascular dysfunction (either IMR≥25 or CFR≤2.0 with FFR>0.80). The primary outcome was the composite of death or re-transplantation at 10years. At baseline, 5.5% had reduced FFR; 36.6% had microvascular dysfunction. Baseline reduced FFR [adjusted hazard ratio (aHR) 2.33, 95% confidence interval (CI) 0.88-6.15; P=0.088] and microvascular dysfunction (aHR 0.88, 95% CI 0.44-1.79; P=0.73) were not predictors of death and re-transplantation at 10years. At 1year, 5.0% had reduced FFR; 23.8% had microvascular dysfunction. One-year reduced FFR (aHR 2.98, 95% CI 1.13-7.87; P=0.028) and microvascular dysfunction (aHR 2.33, 95% CI 1.19-4.59; P=0.015) were associated with significantly increased risk of death or re-transplantation at 10years. Invasive measures of coronary physiology improved the prognostic performance of clinical variables (χ2 improvement: 7.41, P=0.006). However, intravascular ultrasound-derived changes in maximal intimal thickness were not predictive of outcomes.Abnormal coronary physiology 1year after heart transplantation was common and was a significant predictor of death or re-transplantation at 10years.
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| 6. |
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| 7. |
- Arora, Satish, et al.
(författare)
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Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients
- 2018
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Ingår i: Circulation. Heart failure. - 1941-3297. ; 11:9, s. 004050-004050
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Tidskriftsartikel (refereegranskat)abstract
- Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.
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| 8. |
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| 9. |
- Bollano, Entela, 1970, et al.
(författare)
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Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial.
- 2024
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Ingår i: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. - 1557-3117.
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Tidskriftsartikel (refereegranskat)abstract
- Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse.In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study.A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73m2 and 61.0 (52.3-69.7) ml/min/1.73m2 in the everolimus and CNI group, respectively (p<0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p=0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p=0.99).De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.
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| 10. |
- Broch, Kaspar, et al.
(författare)
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Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients : Design of the randomized controlled EVOLVD trial
- 2020
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Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 34:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients. Methods: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4-8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2, renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-month treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound. Conclusion: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.
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