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.

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.

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.

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.

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.

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.

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.

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.

Pharmacologic Management of Aneurysms.

Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm identified hundreds of candidate strategies for stabilization, and data from preoperative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome-related aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field.

Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial.

AIMS: 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 (ß-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 ß-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 ß-blocker use in a multivariate analysis. CONCLUSION: These results suggest a clinical benefit of combined losartan and ß-blocker treatment in patients with MFS.

Racial and ethnic differences in response to treatment for Marfan syndrome.

OBJECTIVE: To determine whether racial/ethnic differences exist for the treatment of Marfan syndrome aortopathy. The 2014 Pediatric Heart Network randomised trial of losartan versus atenolol in Marfan syndrome paediatric and young adult patients showed no treatment differences in the rate of aortic root growth over 3 years; however, they did not examine racial/ethnic differences, and recent data suggest that angiotensin receptor blockers may have different pharmacologic effects in different racial/ethnic populations. METHODS: We performed a secondary analysis of public-use data from the Pediatric Heart Network randomised trial comparing the differences by race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic patients) amongst the treatment groups for the primary outcome of rate of aortic root enlargement by z score and secondary outcome of rate of change of absolute diameter of aortic root, z score and absolute diameter of ascending aorta, and blood pressure changes. RESULTS: For aortic root enlargement by z score amongst non-Hispanic White patients, patients on losartan exhibited an annual z score change of -0.090 ± 0.016, compared to -0.146 ± 0.015 for those on atenolol (p = 0.01), favouring atenolol. For Hispanic and non-Hispanic Black patients, there was no difference in primary or secondary outcomes between treatment groups. CONCLUSION: Non-Hispanic White patients had a small, but statistically significantly greater decrease in aortic root z score favouring atenolol over losartan. There were no significant differences amongst Hispanic or non-Hispanic Black patients, which may be due to relatively small size numbers. These findings may have important implications for medication selection by race/ethnicity in Marfan syndrome patients, which has not previously been evaluated in studies.

Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-ß Pathway.

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor ß (TGF-ß) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking ß blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. FUNDING: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-ß signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.

Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network's Marfan Trial experience.

BACKGROUND/AIMS: The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. METHODS: Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. RESULTS: Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation's resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. CONCLUSION: Overall adherence was excellent for this trial conducted within a National Institutes of Health-funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

The effects of losartan versus beta-blockers on cardiovascular protection in marfan syndrome: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Variable effects of beta-blockers (BB) and/or angiotensin receptor blockers (ARB) were reported to retard aortic root growth in Marfan syndrome (MFS). This study aimed to compare the effects of BB therapy and ARB-related therapies on cardiovascular protection in MFS. METHODS: Studies of randomized control trials comparing the efficacy of only-BB and ARB-related (only-ARB or ARB-plus-BB) therapies for MFS published before July 31, 2018 in PubMed, Embase, and the Cochrane Library were selected. The outcomes included changes in aortic growth and cardiovascular events. RESULTS: Eight trials involving 1381 patients were included. Patients received only-BB and ARB-related therapies did not differ significantly in changes in aortic growth (aortic root diameter: standardized mean difference [SMD] = 0.04, 95% confidence interval [CI]: -0.11-0.19, p = 0.63) or cardiovascular events (aortic dissection: Peto odds ratio [OR] = 1.67, 95% CI: 0.42-6.72, p = 0.47; aortic surgery: risk ratio = 0.97, 95% CI: 0.66-1.41, p = 0.86; death: Peto OR = 2.78, 95% CI: 0.39-19.82, p = 0.31). Subgroup analysis revealed that ARB-plus-BB therapy exhibited nonsignificantly better outcomes than only-BB therapy (aortic root diameter: SMD = 0.11, 95% CI: -0.22-0.45, p = 0.52; ascending aorta diameter: SMD = 0.10, 95% CI: -0.07-0.27, p = 0.26; aortic surgery: Peto OR = 1.10, 95% CI: 0.75-1.61, p = 0.62). CONCLUSION: For cardiovascular protection in MFS, only-ARB therapy is not inferior to only-BB therapy. Moreover, the outcomes of ARB-plus-BB therapy seemed to be favourable to those of only-BB therapy.

Patients at Risk for Aortic Rupture Often Exposed to Fluoroquinolones during Hospitalization.

Several studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection (AAD). Because patients with AAD or Marfan syndrome are at increased risk for aortic rupture, we performed a retrospective cohort study to determine the prevalence of systemic fluoroquinolone exposure and predictors of fluoroquinolone use in these patients. Data were obtained from the advisory board billing and administrative database, which contained information on 22 million adult hospitalizations in the United States for the study period (2009 to 2015). International Classification of Diseases (9/10) and Current Procedural Terminology codes were used to identify patients who had AAD or Marfan syndrome or underwent aortic repair. We identified 136,789 admissions for AAD, which involved 99,818 unique patients, 20% of whom received fluoroquinolone during a hospital admission. Of the 7,045 patients with dissection, 18% were exposed to fluoroquinolone. Of the 27,876 AAD patients who underwent aortic repair, 19% received fluoroquinolone during a hospitalization before the repair. In the AAD patients, having a diagnosis of pneumonia or urinary tract infection increased the likelihood of receiving fluoroquinolone during admission by 46% and 40%, respectively (P < 0.001). Additionally, we identified 2,871 admissions for Marfan syndrome, which involved 1,872 patients, 14% of whom received fluoroquinolone during an admission. In these patients, pneumonia and urinary tract infections also increased the risk of fluoroquinolone exposure. If the deleterious effects of fluoroquinolone on aortic integrity are substantiated, reducing fluoroquinolone use in hospitalized patients with aortic disorders will become an urgent safety issue for antibiotic stewardship programs.

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function.

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome.

OBJECTIVE: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. STUDY DESIGN: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. RESULTS: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P < .001) domains; mean psychosocial scores for adults (19-25 years) were greater than healthy norms (P < .001). HRQOL across multiple domains correlated inversely with frequency of patient-reported symptoms (r = 0.30-0.38, P < .0001). Those <18 years of age with neurodevelopmental disorders (mainly learning disability, attention-deficit/hyperactivity disorder) had lower mean PedsQL scores (5.5-7.4 lower, P < .04). A multivariable model found age, sex, patient-reported symptoms, and neurodevelopmental disorder to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z score, number of skeletal features, or presence of ectopia lentis. CONCLUSIONS: Children and adolescents with Marfan syndrome were at high risk for impaired HRQOL. Patient-reported symptoms and neurodevelopmental disorder, but not treatment arm or severity of Marfan syndrome-related physical findings, were associated with lower HRQOL.