10 research outputs found
Marfan syndrome: The complex road to an optimal treatment strategy
No full textMarfan syndrome (MFS) is a heritable connective tissue disorder affecting the ocular, skeletal and cardiovascular system. The management of patients with MFS requires a multidisciplinary approach, and includes physical symptoms, as well as psychological factors. Optimal long-term outcome in patients with MFS is mainly focused on slowing down the aortic root dilatation rate, and to prevent aortic complications. It demands lifelong follow-up, with imaging of the aortic root at regular intervals, and in many patients lifelong pharmacological treatment, and surgery at young age. It is however intriguing that in this era of drug development, no pharmacological treatment strategy has been identified that can inhibit aortic disease in patients with MFS. Therefore, the main objective of this thesis is to obtain more insight into a novel pharmacological strategy. Furthermore, it is of great importance to establish parameters that could help to determine aortic disease severity in patients with MFS, in order to provide an optimal treatment strategy for individual patients. In that light we also aim to obtain more insight into biomarkers that potentially, identify patients at high risk for aortic complications
Angiographic and clinical outcomes of antegrade versus retrograde techniques for chronic total occlusion revascularizations: Insights from the PRISON IV trial
No full textObjectives: Available data indicate mixed outcomes after using retrograde techniques for chronic total occlusion(CTO) recanalization, with generally higher need for repeat revascularization. Aim of this study is to analyze the angiographic and clinical outcome of patients treated with retrograde techniques in the PRISON-IV trial. Methods and Results: This is a post-hoc sub-analysis from the randomized PRISON-IV trial. Briefly, 330 patients with a successfully recanalized CTO lesion were randomized 1:1 to receive either hybrid-SES or EES. The hybrid-SES failed to reach the non-inferiority primary endpoint of in-segment late lumen loss at 9-month angiography follow-up. In the present analysis, we divided the population according to the first technical approach, namely antegrade (n = 285) or retrograde approach (n = 45). Demographic characteristics were similar between the two groups, while angiographic features disclosed higher CTO lesion complexity in the group treated with retrograde techniques (J-CTO score: 1.8 ± 1.1 vs 2.6 ± 1.1, respectively, P < 0.001), with longer occlusions (17.6 ± 10 mm vs 28.8 ± 18.7 mm, P < 0.001) and longer stented segment (48.9 ± 24.4 mm vs 73.1 ± 33.2 mm, P < 0.001). Quantitative coronary analysis disclosed similar results at follow-up angiography, with a non-significantly higher in-stent late-lumen loss in the retrograde group (0.08 ± 0.52 mm vs 0.18 ± 0.56 mm, P = 0.32). Clinical follow-up at 12-months showed similar outcome, with a non-significantly higher target-lesions revascularization rate in the retrograde group (6% vs 11.1% respectively, P = 0.2). Significant improvements in angina functional class were observed in both groups. Conclusions: The present analysis supports the benefits of retrograde techniques in CTO revascularization, with non-significant differences in angiographic and clinical outcomes at late follow-up
The potential beneficial effects of resveratrol on cardiovascular complications in marfan syndrome patients–insights from rodent-based animal studies
No full textMarfan syndrome (MFS) patients are at risk for cardiovascular disease. In particular, for aortic aneurysm formation, which ultimately can result in a life-threatening aortic dissection or rupture. Over the years, research into a sufficient pharmacological treatment option against aortopathy has expanded, mostly due to the development of rodent disease models for aneurysm formation and dissections. Unfortunately, no optimal treatment strategy has yet been identified for MFS. The biologically-potent polyphenol resveratrol (RES), that occurs in nuts, plants, and the skin of grapes, was shown to have a positive effect on aortic repair in various rodent aneurysm models. RES demonstrated to affect aortic integrity and aortic dilatation. The beneficial processes relevant for MFS included the improvement of endothelial dysfunction, extracellular matrix degradation, and smooth muscle cell death. For the wide range of beneficial effects on these mechanisms, evidence was found for the following involved pathways; alleviating oxidative stress (change in eNOS/iNOS balance and decrease in NOX4), reducing protease activity to preserve the extracellular matrix (decrease in MMP2), and improving smooth muscle cell survival affecting aortic aging (changing the miR21/miR29 balance). Besides aortic features, MFS patients may also suffer from manifestations concerning the heart, such as mitral valve prolapse and left ventricular impairment, where evidence from rodent models shows that RES may aid in promoting cardiomyocyte survival directly (SIRT1 activation) or by reducing oxidative stress (increasing superoxide dismutase) and increasing autophagy (AMPK activation). This overview discusses recent RES studies in animal models of aortic aneurysm formation and heart failure, where different advantageous effects have been reported that may collectively improve the aortic and cardiac pathology in patients with MFS. Therefore, a clinical study with RES in MFS patients seems justified, to validate RES effectiveness, and to judge its suitability as potential new treatment strategy
Aortic distensibility in Marfan syndrome: a potential predictor of aortic events?
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Genome-wide methylation patterns in Marfan syndrome
No full textBackground Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process. Methods The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed. Results We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP's that associated with clinical events. No significant associations at p < 10(-8) or p < 10(-6) were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18-22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before. Conclusion This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.</p
Aortic Function in a Longitudinal 4D Flow MRI Study in Marfan Syndrome Patients Receiving Resveratrol
No full textBackground: New treatment strategies are required to reduce aortic events in Marfan syndrome (MFS). Resveratrol is a dietary supplement that intervenes in aortic wall cellular metabolism and may benefit MFS patients.Purpose: To evaluate whether treatment with Resveratrol affects aorta hemodynamics derived from 4D flow MRI in MFS.Study Type: Prospective single-arm open-label multicenter trial.Population: 46 MFS patients (mean age 36 ± 9 years, 23 female), 20 with and 26 without a history of aortic root surgery (RR and native MFS), and 25 age- and sex-matched healthy controls.Field Strength/Sequence: 3T, temporally resolved 3D phase contrast (4D flow MRI) and 3D mDixon sequences.Assessment: MFS patients underwent 4D flow MRI before (baseline) and after 1 year of 500 mg daily Resveratrol treatment (follow-up). Velocity magnitude and wall shear stress (WSS) in six regions in the thoracic aorta were evaluated. Incidence maps showing abnormal hemodynamics compared to healthy controls were generated. Pulse wave velocity (PWV) was assessed in 45 subjects. The relationships between MRI parameters and annual aortic growth from the 3D mDixon scans and age were investigated.Statistical Tests: Student's paired and unpaired t-tests, Fisher's exact tests, McNemar's exact test, and Pearson correlation coefficients (r). Statistical significance was defined as p < 0.05.Results: No significant changes in any of the hemodynamic parameters were observed: inner descending aorta WSS (Pa), native: from 1.08 ± 0.21 to 1.08 ± 0.17, p = 0.818, RR: from 1.02 ± 0.29 to 0.98 ± 0.21, p = 0.270; velocity (m/s), native: from 0.64 ± 0.10 to 0.65 ± 0.10, p = 0.359, RR: 0.68 ± 0.15, to 0.67 ± 0.12, p = 0.629; abnormally directed WSS incidence: native: from 17 (65%) to 14 (54%), p = 0.453, RR: 13 (65%) to 13 (65%), p = 1.000; PWV (m/s) native: from 7.7 ± 1.9 to 7.9 ± 1.8, p = 0.582, RR: 9.2 ± 1.6 to 8.2 ± 3.2, p = 0.184. PWV correlated with age in RR MFS patients (r = 0.59, n = 19).Data Conclusion: No significant changes in aortic hemodynamics derived from 4D flow MRI were observed after 1 year of Resveratrol treatment.Evidence Level: 1.Technical Efficacy: Stage 4.</p
Additional file 1 of Genome-wide methylation patterns in Marfan syndrome
No full textAdditional file 1. Supplemental material
A cross-sectional study on fatigue, anxiety, and symptoms of depression and their relation with medical status in adult patients with Marfan syndrome:Psychological consequences in Marfan syndrome
No full textMarfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p < 0.0001). There were no differences in HADS anxiety or depression scores. In older MFS patients, with a more severe cardiovascular phenotype, chronic pain, and a higher unemployment rate, significantly more symptoms of depression were observed, when compared with the general population (p = 0.027) or compared with younger MFS patients (p = 0.026). Multivariate analysis, showed that anxiety was associated with chronic pain (p = 0.022) and symptoms of depression with unemployment (p = 0.024). MFS patients report significantly more severe fatigue as compared with the general population. Since the cause of fatigue is unclear, more research may be needed. Psychological intervention, for example, cognitive behavioral therapy, may contribute to a reduction in psychological symptoms.</p
Abnormal aortic hemodynamics are associated with risk factors for aortic complications in patients with marfan syndrome
No full textBACKGROUND: It is difficult to assess the risk for aortic dissection beyond the aortic root in patients with Marfan syndrome (MFS). To aid risk assessment in these patients, we investigated aortic flow and wall shear stress (WSS) by 4D flow magnetic resonance imaging (MRI) in patients with MFS and compared the results with healthy volunteers. We hypothesized that MFS patients with a high-risk profile for aortic dissection would show abnormal hemodynamics in aortic regions associated with aortic dissection. METHODS: MFS patients (n = 55) and healthy subjects (n = 25), matched for age and sex, prospectively underwent 4D flow MRI. 4D flow maps were constructed to detect elevated (defined as higher than the three-dimensional 95 % confidence interval) and deviant directed (defined as vector angle differences higher than 120°) WSS in MFS patients as compared to the controls. Univariate and multivariate associations with risk factors for aortic dissection in MFS patients were assessed. RESULTS: The maximum incidence for elevated WSS was 20 % (CI 9 %-31 %) and found in the ascending aorta. The maximum for deviant directed WSS was 39 % (CI 26 %-52 %) and found in the inner descending aorta. Significantly more male patients had deviant directed WSS in the inner proximal descending aorta (63 % vs 24 %, p = 0.014). Multivariate analysis showed that deviant directed WSS was associated with male sex (p = 0.019), and a haplo-insufficient FBN1 mutation type (p = 0.040). In 60 % of MFS patients with a previous aortic root replacement surgery, abnormal hemodynamics were found in the ascending aorta. No significant differences between hemodynamics were found in the descending aorta between operated and non-operated patients. CONCLUSION: Deviant directed WSS in the proximal descending aorta is associated with known risk factors for aortic dissection in MFS patients, namely male sex and a haploinsufficient FBN1 mutation type
Long-term clinical outcomes of losartan in patients with Marfan syndrome:follow-up of the multicentre randomized controlled COMPARE trial
No full textAIMS: The COMPARE trial showed a small but significant beneficial effect of 3-year losartan treatment on aortic root dilatation rate in adults with Marfan syndrome (MFS). However, no significant effect was found on clinical endpoints, possibly due to a short follow-up period. The aim of the current study was therefore to investigate the long-term clinical outcomes after losartan treatment.METHODS AND RESULTS: In the original COMPARE study (inclusion 2008-2009), adult patients with MFS (n = 233) were randomly allocated to either the angiotensin-II receptor blocker losartan® on top of regular treatment (β-blockers in 71% of the patients) or no additional medication. After the COMPARE trial period of 3 years, study subjects chose to continue their losartan medication or not. In a median follow-up period of 8 years, 75 patients continued losartan medication, whereas 78 patients, originally allocated to the control group, never used losartan after inclusion. No differences existed between baseline characteristics of the two groups except for age at inclusion [losartan 34 (interquartile range, IQR 26-43) years, control 41 (IQR 30-52) years; P = 0.031], and β-blocker use (losartan 81%, control 64%; P = 0.022). A pathological FBN1 mutation was present in 76% of patients and 58% of the patients were male. Clinical endpoints, defined as all-cause mortality, aortic dissection/rupture, elective aortic root replacement, reoperation, and vascular graft implantation beyond the aortic root, were compared between the two groups. A per-patient composite endpoint was also analysed. Five deaths, 14 aortic dissections, 23 aortic root replacements, 3 reoperations, and 3 vascular graft implantations beyond the aortic root occurred during follow-up. Except for aortic root replacement, all endpoints occurred in patients with an operated aortic root. Patients who used losartan during the entire follow-up period showed a reduced number of events compared to the control group (death: 0 vs. 5, P = 0.014; aortic dissection: 3 vs. 11, P = 0.013; elective aortic root replacement: 10 vs. 13, P = 0.264; reoperation: 1 vs. 2, P = 0.463; vascular graft implantations beyond the aortic root 0 vs. 3, P = 0.071; and composite endpoint: 14 vs. 26, P = 0.019). These results remained similar when corrected for age and β-blocker use in a multivariate analysis.CONCLUSION: These results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS.</p
