Complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

An exploration of alternative therapeutic targets for aortic disease in Marfan syndrome.

Marfan syndrome is a rare connective tissue disorder that causes aortic dissection-related sudden death. Current conventional treatments, beta-blockers, and type 1 angiotensin II receptor blockers are prescribed to slow down aortic aneurysm progression and delay (prophylactic) aortic surgery. However, neither of these treatments ceases aortic growth completely. This review focuses on potential alternative therapeutic leads in the field, ranging from widely used medication with beneficial effects on the aorta to experimental inhibitors with the potential to stop aortic growth in Marfan syndrome. Clinical trials are warranted to uncover their full potential.

Evaluating Variation in the Cardiac Management of Children with Hereditary Thoracic Aortic Disease in the United States.

Hereditary thoracic aortic diseases (HTAD) such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and vascular Ehlers-Danlos syndrome (VEDS) frequently result in complex cardiovascular pathology that can lead to premature death. However, given limited research and lack of detailed pediatric management guidelines, practice in the U.S. is largely guided by personal experience and/or advice from other professionals. A REDCap survey was composed that covered topics including genetic testing, imaging, and medication choice (all in children), among others. After piloting, the survey was distributed via email and advertised on PediHeartNet. Email addresses of providers were obtained through an established aortic research collaborative and a clinic directory offered through The Marfan Foundation. There were 64 survey responses (pediatric cardiologists 66%; geneticists 13%, genetic counselors 6%; the remaining 15% was comprised of a combination of cardiothoracic surgeons, adult cardiologists, adult congenital specialists, combined cardiology and genetics specialist, nurse practitioners, physician assistants, and nurse coordinators). The most supported indication for genetic evaluation in a child with mild aortic root dilation was family history of thoracic aortic dissection (100%), in contrast to mild root dilation with no other HTAD features (39% supported, 45% did not, 15% saying it would depend on other factors). The majority would start medical therapy in MFS at an aortic root z-score of 2, however differences existed regarding medication preferences for initiation (47% angiotensin receptor blockers, 36% beta blockers, 17% would not or cannot prescribe medication/defer medication choice to another provider). Variation existed for cross-sectional imaging indications and modality and for exercise restrictions, although on average respondents were more lenient than the Bethesda guidelines. While there are areas of general agreement in the cardiac management of children with HTAD, there are also several areas of considerable variation. This highlights the need for additional study in these areas with the ultimate goal of creating consensus guidelines.

17 ß-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice.

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 ß-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 ß-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 ß-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 ß-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 ß-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 ß-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 ß-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 ß-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling.

Successful treatment of post-pericardiotomy syndrome via C1 inhibitor replacement therapy in a hereditary angioedema patient with Marfan syndrome.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is caused by dysfunctional C1-INH protein due to mutations in the SERPING1 gene encoding C1-INH. Marfan syndrome is a genetic connective tissue disease that affects the cardiovascular and ocular systems along with the skeletal system. In this case, we present the successful treatment of post-pericardiotomy syndrome unresponsive to classical therapy, which has not been described in the literature. The syndrome developed in a patient with hereditary angioedema (HAE) who underwent open heart surgery due to cardiac involvement in Marfan syndrome. CASE: A nine-year-old male HAE-C1INH patient underwent open heart surgery secondary to cardiac involvement caused by Marfan syndrome. To prevent HAE attacks, 1000 units of C1 inhibitor concentrate therapy were given 2 hours before and 24 hours after the operation. Post-pericardiotomy syndrome was diagnosed on the postoperative second day and ibuprofen 15 mg/kg/day (3 weeks) was started. Since there was no response to classical treatment on the 21st postoperative day, C1 inhibitor concentrate treatment was planned as 1000 units/ dose for 2 days a week considering a prolonged hereditary angioedema attack. In the second week of treatment, complete recovery was achieved for pericardial effusion with a total of 4 doses. CONCLUSIONS: We emphasize that in patients with hereditary angioedema undergoing this treatment, care should be taken in terms of complications that may be associated with the disease even if short-term prophylaxis is given before operations and that longer-term use of C1 inhibitor concentrate has a place in treatment.

Drug-based cardiovascular prevention in patients with Marfan Syndrome: a systematic review.

INTRODUCTION: Marfan Syndrome (MFS) is a rare and complex genetic disorder associated with increased aortic growth and aortic disease. The effectiveness of cardiovascular medical therapies aiming to slow down aortic growth has been tested in several trials, particularly beta-blockers and angiotensin receptor blockers, however showing conflicting results. EVIDENCE ACQUISITION: We conducted a systematic review on PubMed (Medline), Cochrane library, Google Scholar, and Biomed Central databases between January and February 2022. We selected relevant articles focusing on patients with MFS treated with beta-blockers, angiotensin receptors blockers, or both, and reporting data on the effect of the drugs on 1) slowing down aortic dilatation; 2) the reduction of aortic complication (aortic dissection, mortality, aortic surgery); and with a 3) follow-up length of at least two years. A total of 16 studies were selected. EVIDENCE SYNTHESIS: Beta-blockers remain the mainstay of therapy as they have proven to slow aortic enlargement. Angiotensin receptor blockers are a useful alternative and with proven benefit as an add-on therapy to limit aortic growth. Neither beta-blockers, nor angiotensin receptor blockers have shown meaningful results on clinical aortic endpoints. CONCLUSIONS: The current evidence of pharmacological treatment for MFS patients is conflicting due to the lack of large, randomized clinical trials with adequate follow-up studies and homogeneous age grouping. Beta-blockers and angiotensin receptor blockers are the only available treatments to reduce aortic growth. A recently published patient-level meta-analysis confirmed that angiotensin receptor blockers and beta-blockers have a similar effect on reducing the rate of increase of the aortic root Z score, used singularly or as add-on therapy. Considering the current evidence on new features related with MFS (such as mitral annular disjunction - MAD) bearing a potential additional increased arrhythmic risk, it is of paramount importance to establish the role of beta-blockers and angiotensin receptor blockers in clinical endpoints of this population as well.

Pediatric Heart Network Trial of Losartan vs. Atenolol in Children and Young Adults with Marfan Syndrome: Impact on Prescription Practices.

The Pediatric Heart Network (PHN) trial showed similar efficacy of ß-blockers (BB) and angiotensin receptor blockers (ARB) for aortic root dilation in Marfan syndrome, but the impact on prescription practices is unknown. We hypothesized BB and ARB prescriptions would increase after the trial results were published (2014). Prescription data (2007-2016) were obtained from outpatient encounters (IBM Marketscan) for Marfan syndrome patients (6 months-25 years old). Excluding 2014 as a washout period, we analyzed two intervals: 2007-2013 and 2015-2016. Medication categories included BB, ARB, angiotensin converting enzyme inhibitors (ACEI), combination (BB/ARB and/or BB/ACEI), and no drug. Interrupted time-series analysis assessed immediate level change after publication and change in slope for the trend pre- and post-publication. Odds ratios (OR) and 95% confidence intervals from logistic regressions and generalized estimating equation methods accounted for correlation of prescriptions within patients. In 1499 patients (age 14.1 ± 6.1 years, 59% female) seen 2007-2013, BB trended lower [OR 0.91 (0.89, 0.93), p < 0.001] and ARB trended higher [OR 1.12 (1.07, 1.18), p < 0.001], while combination, ACEI, and no drug remained stable. This trend persisted, but was not significant, for BB [OR 0.54 (0.27, 1.08), p = 0.37] and ARB [OR 1.91 (0.55, 6.69), p = 0.31] in 2015-2016. Combination, ACEI, and no drug remained similar. In short term follow-up, changes in prescription practices following publication of the PHN trial were not statistically significant. This may be due to a change seen prior to publication with early adoption of ARBs that was maintained after confirmation of their effectiveness.

Case Report: Effects of Sars-CoV-2 on Marfan syndrome with resulting acute aortic dissection.

Marfan syndrome is one of the most common inherited connective tissue disorders that affects the heart, eyes, blood vessels, and bones. It occurs in approximately 1-2 per 10,000 individuals annually. Many patients with Marfan syndrome eventually develop aortic wall abnormalities, often resulting in aortic dilatation, which increases the risk of acute aortic dissection. Recent studies involving SARS-CoV-2 propose that individuals with connective tissue disorders such as Marfan syndrome can have additional associated conditions that could impose a higher risk for morbidity and mortality from SARS-CoV-2. The purpose of this article is to discuss the interrelationship between Marfan Syndrome, Acute Type A Aortic Dissection in a patient with Sars-CoV-2 infection. Pertinent review of these conditions, diagnostic findings, treatment, and the patient's clinical course will be discussed. There is minimal research focused on the connection between this novel virus, Marfan Syndrome, and compounding risk for aortic dissection.

Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice. METHODS: Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7-8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta. RESULTS: The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival. CONCLUSIONS: Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.

Angiotensin receptor blockers and ß blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) and ß blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. METHODS: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus ß blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus ß blocker; and indirectly, ß blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. FINDINGS: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with ß-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with ß blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in ß-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between ß blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042). INTERPRETATION: In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a ß blocker. The effects of ß blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and ß blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. FUNDING: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Effects of Rapamycin on the Expression of Redox Enzymes in Aortic Vascular Smooth Muscle Cells from Marfan Syndrome Mice.

Activation of the mechanistic target of rapamycin (mTOR) pathway has been implicated in an increasing number of diseases, including Marfan syndrome (MFS), an inherited connective tissue disorder. mTOR-dependent reactive oxygen species (ROS) formation has also been suggested to play a role in aortic aneurysm formation in MFS patients. This study aimed to characterize the effects of mTOR inhibition by rapamycin on key redox enzymes and NADPH oxidases (NOX) in cultured vascular smooth muscle cells of a murine MFS model. Therefore, the influence of 5 and 20 nmol/L rapamycin solved in 0.1% (vol/vol) DMSO on glutathione peroxidases 1 (Gpx1) and 4 (Gpx4), superoxide dismutase 2 (Sod2), and catalase (Cat) mRNA and protein expression was investigated in isolated murine aortic smooth muscle cells. Rapamycin inhibited the mRNA expression of all redox enzymes by 30-50%, except Gpx1. In the same cells, the mRNA expression of the transcription factor NFE2-related factor-2 and peroxisome proliferator-activated receptor-γ, key factors against oxidative stress, and controlling redox gene expression were also inhibited to a comparable extent under these conditions. In addition, Nox1 but not Nox4 mRNA expression was significantly inhibited by up to 40%. DMSO alone increased nearly 2-fold the redox enzyme protein expression, which was reduced considerably to basal levels by rapamycin. Proteasomal inhibition by bortezomib could not reverse the observed decrease of GPx protein content. The rapamycin-mediated decrease in GPx protein abundance was reflected in a reduced total GPx enzymatic activity. Higher rapamycin concentrations did not further decrease but led to a renewed increase in enzymatic activity despite low GPx protein concentrations. Baseline ROS formation was slightly inhibited at 13% with 5 nmol/L rapamycin and returned to baseline levels with the higher 20 nmol/L rapamycin concentration. In conclusion, this study further characterized the mechanism of action of rapamycin. It provided an insight into how rapamycin interferes with the regulation of redox homeostasis essential for ROS-dependent signaling that does not incur cellular damage.

Oxidative Stress in Plasma from Patients with Marfan Syndrome Is Modulated by Deodorized Garlic Preliminary Findings.

Marfan syndrome (MFS) is a genetic disorder of connective tissue that affects the fibrillin-1 protein (FBN-1). It is associated with the formation of aneurysms, damage to the endothelium and oxidative stress (OS). Allium sativum (garlic) has antioxidant properties; therefore, the goal of this study was to show the antioxidant effect of deodorized garlic (DG) on antioxidant enzymes and OS markers in the plasma of patients with MFS. The activity of antioxidant enzymes such as extracellular superoxide dismutase (EcSOD), peroxidases, glutathione peroxidase (GPx), gluthatione-S-tranferase (GST), and thioredoxin reductase (TrxR) was quantified, and nonenzymatic antioxidant system markers including lipid peroxidation (LPO), carbonylation, nitrates/nitrites, GSH, and vitamin C in plasma were determined in patients with MFS before and after treatment with DG. The results show that DG increased the activity of the EcSOD, peroxidases, GPx, GST, TrxR (p ≤ 0.05) and decrease LPO, carbonylation, and nitrates/nitrites (p ≤ 0.01). However, glutathione was increased (p = 0.01) in plasma from patients with MFS. This suggests that treatment with garlic could lower the OS threshold by increasing the activity of antioxidant enzymes and could help in the prevention and mitigation of adverse OS in patients with MFS.

Angiotensin Receptor Blockers vs. Beta-Blocker Therapy for Marfan Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVE: Several RCTs have been conducted to assess the efficacy and safety of angiotensin receptor blocker (ARB) and beta-blocker (BB) therapy for Marfan syndrome (MFS), but the existing evidence is limited and conflicting. This study aimed to compare the efficacy and safety of different therapies. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases were electronically searched up to March 2021 to retrieve randomized controlled trials regarding the efficacy and safety of ARB-related (including ARB-only and ARB+BB treatment) and BB-only treatment for treating patients with MFS. The revised risk-of-bias tool was used for quality assessment. The odds ratio (OR) and standard mean difference (SMD) with 95% confidence interval (CI) were used to estimate the pooled effect size. RESULTS: Fourteen reports of 9 trials involving 1,449 patients were included in the meta-analysis. Regarding aortic root dilation, the ARB-related regimen has efficacy comparable with that of the BB-only regimen in patients with MFS (pooled SMD = -0.16, 95% CI [-0.33; 0.01]; P = 0.06), while in the ARB+BB vs. BB-only subgroup, a significant difference was observed (pooled SMD = -0.26; 95% CI [-0.40; -0.11]; P < 0.01). In addition, there were no significant differences in other aortic dilation-related measures (aortic root Z scores, ascending aorta, pulmonary artery, aortic annulus, sinotubular junction, aortic arch, thoracic aorta, and abdominal aorta diameter change) or cardiovascular events (aortic dissection, aortic surgery, and death) between the 2 regimens. CONCLUSION: Our results showed that the clinical efficacy of ARB-only therapy is not inferior to that of BB-only therapy. Moreover, ARB+BB therapy showed superior therapeutic effects without significant adverse effects.

Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome.

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFß signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.

AIMS: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. METHODS AND RESULTS: Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II. CONCLUSION: NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Initial Angiotensin Receptor Blocker Response in Young Marfan Patients Decreases After 3 Years of Treatment.

Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.