Publications by authors named "Christoffer V Madsen"

5 Publications

  • Page 1 of 1

Randomized Trial of Surgical Left Atrial Appendage Closure: Protection Against Cerebrovascular Events.

Semin Thorac Cardiovasc Surg 2022 Jun 28. Epub 2022 Jun 28.

Department of Cardiology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark.

Following open-heart surgery, atrial fibrillation and stroke occur frequently. Left atrial appendage closure added to elective open-heart surgery could reduce the risk of ischemic stroke. We aim to examine if routine closure of the left atrial appendage in patients undergoing open-heart surgery provides long-term protection against cerebrovascular events independently of atrial fibrillation history, stroke risk, and oral anticoagulation use. Long-term follow-up of patients enrolled in the prospective, randomized, open-label, blinded evaluation trial entitled left atrial appendage closure by surgery (NCT02378116). Patients were stratified by oral anticoagulation status and randomized (1:1) to left atrial appendage closure in addition to elective open-heart surgery vs standard care. The primary composite endpoint was ischemic stroke events, transient ischemic attacks, and imaging findings of silent cerebral ischemic lesions. Two neurologists blinded for treatment assignment adjudicated cerebrovascular events. In total, 186 patients (82% males) were reviewed. At baseline, mean (standard deviation (SD)) age was 68 (9) years and 13.4% (n = 25/186) had been diagnosed with atrial fibrillation. Median [interquartile range (IQR)] CHADS-VASc was 3 [2,4] and 25.9% (n = 48/186) were receiving oral anticoagulants. Mean follow-up was 6.2 (2.5) years. The left atrial appendage closure group experienced fewer cerebrovascular events; intention-to-treat 11 vs 19 (P = 0.033, n = 186) and per-protocol 9 vs 17 (P = 0.186, n = 141). Left atrial appendage closure as an add-on open-heart surgery, regardless of pre-surgery atrial fibrillation and oral anticoagulation status, seems safe and may reduce cerebrovascular events in long-term follow-up. More extensive randomized clinical trials investigating left atrial appendage closure in patients without atrial fibrillation and high stroke risk are warranted.
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http://dx.doi.org/10.1053/j.semtcvs.2022.06.012DOI Listing
June 2022

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study.

Nephrol Dial Transplant 2019 09;34(9):1525-1533

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age.

Methods: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included.

Results: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender.

Conclusions: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.
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http://dx.doi.org/10.1093/ndt/gfy357DOI Listing
September 2019

Enzyme Replacement Therapy During Pregnancy in Fabry Patients : Review of Published Cases of Live Births and a New Case of a Severely Affected Female with Fabry Disease and Pre-eclampsia Complicating Pregnancy.

JIMD Rep 2019 17;44:93-101. Epub 2018 Aug 17.

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Fabry disease (FD) is an X-linked, lysosomal storage disease. Mutations in the gene coding for alpha-galactosidase A lead to globotriaosylceramide (Gb-3) accumulation in lysosomes and in placenta and umbilical cord. Impact of FD and treatment with enzyme replacement (ERT) on foetal development is undisclosed.A 38-year-old primigravida with FD (G85N) is reported. She has 50% reduced alpha-galactosidase A activity and elevated plasma and urine-Gb-3. She was severely affected with ischaemic stroke at age 23, hypertension, albuminuria and moderately reduced renal function. ERT was initiated at age 23 years in 2001 and continued during spontaneous pregnancy at age 38. In third trimester she developed moderate-to-severe pre-eclampsia, successfully managed by methyldopa. Chorion villus sampling revealed a male foetus without the maternal gene mutation. Planned Caesarean section was performed without complications at gestational age week 38 + 6, delivering a healthy boy. Histopathological placental examination showed no sign of Gb-3 accumulation. Literature survey disclosed a total of 12 cases, 8 were treated with ERT during pregnancy and 5 infants inherited the family mutation. All outcomes were successful. In the six cases with available placental histopathological examination, Gb-3 accumulation was only seen on the foetal side if the foetus had the inherited mutation.In conclusion, the present case, describing the first data from a severely affected FD patient receiving ERT during pregnancy complicated by pre-eclampsia, together with all other published cases, has emphasized that ERT is safe during pregnancy and resulting in successful foetal outcome; despite this, ERT is by the health authorities advised against during pregnancy.
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http://dx.doi.org/10.1007/8904_2018_129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323029PMC
August 2018

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

Circ Cardiovasc Genet 2017 Aug;10(4)

From the Faculty of Medicine, University of Iceland, Reykjavik, Iceland (B.A., R.P., R.A., G.T.G.); Division of Cardiology (B.A., R.D.), Department of Genetics (R.A.), Division of Nephrology (R.P.), and Department of Radiology (M.G.), Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Department of Cardiology, Haukeland University Hospital, Bergen, Norway (B.A.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.J.D., B.C., S.P.); Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., J.G.S., C.E.S.); Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.A., U.N.); Division of Cardiology, Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (M.M., B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (M.A.B.); Department of Medical Endocrinology, Rigshospitalet and University of Copenhagen, Denmark (C.V.M., U.F.-R.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Department of Medicine, Akureyri Hospital, Iceland (G.T.G.).

Background: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B).

Methods And Results: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations.

Conclusions: Men with classic or later-onset FD caused by missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001639DOI Listing
August 2017

Ophthalmic experience over 10 years in an observational nationwide Danish cohort of Fabry patients with access to enzyme replacement.

Acta Ophthalmol 2015 May 9;93(3):258-64. Epub 2014 Dec 9.

Eye Departments, Rigshospitalet and Glostrup, Copenhagen University, Copenhagen, Denmark.

Purpose: Enzyme replacement therapy (ERT) was offered from year 2001 to patients with Fabry disease. The ophthalmic experience was analysed, as part of a general 10-year status.

Methods: A retrospective observational series comprising 39 patients (25 females, 14 males) closely followed by the endocrinologists, and with regular ophthalmic control. Time of inclusion was when the option of ERT was started, at age 11-60 years. Eye data (standard eye examination, including retinal imaging) were incomplete in five, due to death or non-attendance, and five patients had refused treatment.

Results: Vision was normal throughout, except in two young males with total unilateral central retinal artery occlusion, prior to and during enzyme replacement, respectively. Cornea verticillata and conjunctival vessel ectasies were common. Tortuosity of retinal arterioles and venules was recorded in eight and 18 patients, respectively, and phlebopathy in 22, although generally without evidence of loss of vessel wall integrity. Systemic vascular lesions with or without loss of function were recorded for kidney (n = 23), heart (n = 17) and brain (n = 7), and an association was suggested between nephropathy and abnormal morphology of retinal vessels.

Conclusions: Thirteen of 32 patients on ERT showed a reduction of corneal deposits over the study period. Abnormal ocular vessel morphology was a frequent finding. In contrast to the function loss related to systemic ischaemic lesions, we found no indication of impairment of visual parameters in 37. Compared to other Fabry series, two of 39 patients with serious unilateral occlusive retinal disease may appear a high number. The presence of retinal tortuosity is discussed, possibly reflecting haemodynamic events related to vessel wall deposits, but could also be 'constitutional', as part of the Fabry inheritance.
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http://dx.doi.org/10.1111/aos.12588DOI Listing
May 2015
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