Aortic Root Dilatation Rate Research Articles

17 β-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 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 β-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 β-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 β-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 β-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 β-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 β-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 β-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling.

Can 10 000 Healthy Steps a Day Slow Aortic Root Dilation in Pediatric Patients With Marfan Syndrome?

Background Stiffer aortas are associated with a faster rate of aortic root (AoR) dilation and higher risk of aortic dissection in patients with Marfan syndrome. We have previously shown that mild aerobic exercise reduces aortic stiffness and rate of AoR dilation in a Marfan mouse model. In this study, we investigated if these results could be translated to pediatric patients with Marfan syndrome. Methods and Results We enrolled 24 patients with Marfan syndrome aged 8 to 19 years to participate in a 6-month physical activity intervention, excluding those with ventricular dysfunction or prior history of aortic surgery. We instructed patients to take 10 000 steps per day, tracked by an activity tracker. At baseline and 6 months, we measured AoR dimension, arterial stiffness, endothelial function, physical activity indices, inflammatory biomarkers, and coping scores. Controls consisted of 15 age-matched patients with Marfan syndrome. Twenty-four patients with Marfan syndrome (median age, 14.4 years [interquartile range {IQR}, 12.2-16.8], 14 male patients) were enrolled. Baseline assessment demonstrated that the majority of these patients were sedentary and had abnormal arterial health. Twenty-two patients completed the intervention and took an average of 7709±2177 steps per day (median, 7627 [IQR, 6344-9671]). Patients wore their Garmin trackers at a median of 92.8% (IQR, 84%-97%) of their intervention days. AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01). Conclusions In this clinical intervention in pediatric patients with Marfan syndrome, we demonstrated that a simple physical activity intervention was feasible in this population and has the potential to decrease the AoR dilation rate. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03567460.

Identification of a common polymorphism in COQ8B acting as a modifier of thoracic aortic aneurysm severity.

SummaryThoracic aortic aneurysm (TAA) predisposes to sudden, life-threatening aortic dissection. The factors that regulate interindividual variability in TAA severity are not well understood. Identifying a molecular basis for this variability has the potential to improve clinical risk stratification and advance mechanistic insight. We previously identified COQ8B, a gene important for biosynthesis of coenzyme Q, as a candidate genetic modifier of TAA severity. Here, we investigated the physiological role of COQ8B in human aortic smooth muscle cells (SMCs) and further tested its genetic association with TAA severity. We find COQ8B protein localizes to mitochondria in SMCs, and loss of mitochondrial COQ8B leads to increased oxidative stress, decreased mitochondrial respiration, and altered expression of SMC contractile genes. Oxidative stress and mitochondrial cristae defects were prevalent in the medial layer of human proximal aortic tissues in individuals with TAA, and COQ8B expression was decreased in TAA SMCs compared with controls. A common single nucleotide polymorphism (SNP) rs3865452 in COQ8B (c.521A>G [p.His174Arg]) was associated with decreased rate of aortic root dilation in young individuals with TAA. In addition, the SNP was less frequent in a second cohort of early-onset thoracic aortic dissection (TAD) cases compared with controls. COQ8B protein levels in aortic SMCs were increased in TAA individuals homozygous for rs3865452 compared with those homozygous for the reference allele. Thus, COQ8B is important for aortic SMC metabolism, which is dysregulated in TAA, and rs3865452 may decrease TAA severity by increasing the COQ8B level. Genotyping rs3865452 may be useful for clinical risk stratification and tailored aortopathy management.

The Late Effects of Pregnancy on Aortic Dimensions in Patients with Marfan Syndrome

While the immediate effects of pregnancy on aortic dimension in patients with Marfan syndrome (MFS) have been evaluated, the late effects of subsequent pregnancies in these patients are less known. For this purpose, we evaluated 2 groups of women with MFS who were under specialized care in our institution. Group A included 23 women with MFS who experienced 55 pregnancies; group B included 12 nulliparous MFS patients. Patients in group A were similar in age (36.13 ± 5.6 years vs. 34.25 ± 6.54 years, p = 0.41) and follow-up time (group A 6.05 ± 3.56 years and group B 4.92 ± 3.37 years, p = 0.37). Baseline aortic root diameters as well as the aortic root diameters at follow-up visits were similar between groups (35.60 ± 4.42 vs. 35.08 ± 3.82 mm, p = 0.73, and 37.57 ± 4.66 vs. 37.33 ± 4.83 mm, p = 0.89, respectively). The aortic root diameter increased by 0.5 (0, 2) mm in group A and 1 (0, 4.5) mm in group B (p = 0.54). The rate of aortic dilation per year of follow-up was similar between the groups (0.34 ± 0.52 mm/year in group A vs. 0.55 ± 0.75 mm/year in group B [p = 0.52]). Chronic medical treatment was similar in both groups. Patients in both groups were treated similarly with β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. In summary, subsequent pregnancies in patients with MFS were not associated with an increase in the rate of aortic root dilation in these patients.

Abstract 13562: COQ8B : A Candidate Genetic Modifier of Thoracic Aortic Aneurysm Severity

Thoracic aortic aneurysm (TAA) is a latent aortopathy that predisposes to life-threatening aortic dissection. Personalized prediction of the risk for progressive aortic dilation and dissection is currently limited. The identification of genetic modifiers may facilitate more precise risk prediction and optimize clinical decisions. We previously identified COQ8B , a gene important for mitochondrial biosynthesis of coenzyme Q, as a candidate modifier of TAA severity. Biological evidence for a mitochondrial role in TAA pathogenesis includes severe mitochondrial ultrastructural defects in aortic smooth muscle cells (SMCs) and nitrated tyrosine residues in TAA tissues consistent with oxidative stress. In this study, we hypothesized that a common single nucleotide polymorphism (SNP) rs3865452 in COQ8B (c.521A>G, p.H174R) modifies the rate of aortic root dilation. Forty-eight patients with TAA and a mean age at first echocardiogram of 10 ± 5 years were genotyped for rs3865452. Echocardiograms (mean 6.8 ± 4.0 per patient) were performed clinically over a mean interval of 5.3 ± 4.1 years. In mixed model analysis of longitudinal aortic root Z-scores, the c.521G allele was associated with a decreased rate of aortic root dilation in univariate analysis (p=0.0003) and multivariate analysis (p=0.03) that included sex and genetic syndrome as covariates. Hypothesizing a modifier role for COQ8B , we analyzed a separate cohort of 230 individuals with early onset thoracic aortic dissection. The c.521G allele was less frequent in dissection cases than controls (p=0.04), also consistent with a protective effect for this SNP. To better understand the mechanism of COQ8B effect in TAA, RNA levels of COQ8B in SMCs cultured directly from the aorta were assayed, demonstrating levels 2-fold lower in TAA compared with controls. siRNA knockdown of COQ8B in aortic SMCS resulted in decreased mitochondrial respiration, increased lipid peroxidation, and altered expression of SMC contractile genes. In conclusion, the findings of this study support a modifier role for the rs3865452 SNP in COQ8B in TAA, which may involve mitochondrial pathology and oxidative stress. This suggests that this SNP may be useful for clinical risk prediction.

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

AimsThe 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 resultsIn 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.ConclusionThese results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS.

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

SummaryBackgroundIrbesartan, 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.MethodsWe 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.FindingsBetween 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 β 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.InterpretationIrbesartan 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.FundingBritish Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Root reconstruction for proximal repair in acute type A aortic dissection.

Retrospective compared the results of root reconstruction and root replacement for acute type A aortic dissection (ATAAD) patients and observed the rate of aortic insufficiency (AI) and aortic root dilation in the midterm follow-up period. From 2008-2016, 427 ATAAD patients received surgical therapy in our center. There were 328 male and 99 female patients, aging from 22 to 83 years with a mean age of (51.1±12.5) years. These patients were divided into two major groups: 298 cases with root reinforcement reconstruction (Root Reconstruction), 129 cases with Bentall procedure (Root Replacement). The 30-day mortality was 7.7% (33/427), while no difference between the 2 procedures (8.1% and 7.0%, P=0.844). Cross-clamp, cardiopulmonary bypass, and circulatory arrest times of all the patients were 252.5±78.1, 173.6±68.9, 30.7±9.5 minutes, respectively. In the average follow-up time of (34.5±26.1) months, midterm survival rates were similar between the 2 procedures (86.2% and 86.0%, P=0.957). Only one patient received redo Bentall procedure because of severe aortic regurgitation and dilated aortic root (50 mm) in the Root Reconstruction Group. The indication of root management of ATAAD is based on the diameter of aortic root, structure of aortic root, and the dissection involvement. For most ATAAD patients, aortic root reinforcement reconstruction is a feasible and safe method.

445Effects of losartan and beta-blockers on aortic root dilatation in patients with Marfan Syndrome - results of the extended COMPARE trial

Abstract Introduction Despite several randomized trials, beneficial effects of Losartan and β-blockers in adults with Marfan syndrome (MFS) are not entirely clear. The COMPARE trial previously showed a small but significant beneficial effect of Losartan on top of β-blocker use on aortic root dilatation rate. Yet, this effect was not reproduced by other trials, although in general a favourable effect of Losartan could be demonstrated. All trials in adults with MFS showed lower than expected aortic root dilatation rates, suggesting mildly affected study populations. Therefore we extended the follow-up period of the COMPARE trial up to 10 years and aimed to assess the clinical outcomes of the study cohort, as well as the effect of medication regimes on aortic root dilatation rates in the subgroup of patients with a native aortic root at initial randomization. Methods Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events (aortic dissections, ruptures and operations) and all-cause mortality were assessed. Individual aortic root dilatation rates were estimated in patients with a native aortic root at time of randomization on the basis of linear regression analysis of multiple transthoracic echocardiogram (TTE) results. Correlations between aortic root dilatation rates and cumulative Losartan or β-blocker treatment days were assessed with Spearman's rho (ρ). Results During a median follow-up of 8.0 years, two dissections and three deaths occurred in the 151 patients with a native aortic root at time of randomization. The 122 patients that were eligible for aortic root dilatation analysis, underwent a median of 6 TTEs. The median aortic root dilatation rate in these patients was 0.28 (interquartile range 0.09 - 0.59) mm/y. These patients were further classified as either patients with a stable aortic root (n=102) or with aortic root growth (n=20), based on the threshold of 0.9 mm per year. Patients with aortic root growth had significantly more aortic root replacements during follow-up (17/20 vs 18/102, P=0.001). Furthermore, aortic root dilatation rate was negatively correlated with the number of Losartan treatment days (ρ=−0.272, P=0.003), β-blocker treatment days (ρ=−0.217, P=0.017) and with the duration of follow-up (ρ=−0.437, P<0.001). Conclusions Our results support previous findings that Losartan and β-blockers appear to be equally effective on aortic root dilatation rate in Marfan Syndrome patients. The low event rate in the long term follow-up of this subgroup of the COMPARE trial represent a relatively mildly affected study population and an aggressive prophylactic surgical regime.

Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome.

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36months read in the core laboratory of 608 trial subjects, aged 6months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.

Aspekty diagnostyczne i terapeutyczne zespołu Marfana w wieku rozwojowym

Marfan’s syndrome (MFS) is a systemic, autosomal dominant connective tissue disease. It is caused mainly by the mutations in the FBN1 gene and is connected with extracellular matrix protein fibrillin-1. The incidence is about 2-3 per 10 000. About 70-75% of cases are inherited in an autosomal dominant fashion and the remaining are de-novo mutations. The most common findings involve cardiovascular, ocular and skeletal systems. The cardinal manifestations typically involving MFS are aortic root aneurysm/dissection and ectopia lentis. The other common manifestations are mitral valve prolapse, proximal aortic aneurysm, dolichocephaly, pectus carinatum deformity, enophthalmos, scoliosis, long-bone overgrowth. The manifestation in neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is a rapidly progressing multi-valvular cardiac disease. The death connected with congestive heart failure happens mainly within the first year of life. Prognostic factors for life expectancy of patients with Marfan syndrome depend on the type of the MFS and in classical MFS – depend on the rate of aortic root dilatation, which leads to dissection or rupture. Pharmacological management includes beta blockers, angiotensin receptor blockers and angiotensin converting enzyme inhibitor as a preventive treatment to slow aortic root dilation.

Losartan in combination with propranolol slows the aortic root dilatation in neonatal Marfan syndrome

Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is characterized by rapidly progressive multi-valvular cardiac disease and death from congestive heart failure, typically within the first year of life. Due to the rarity of this condition, treatment for neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan and propranolol reduced the aortic root dilatation rate after three months of losartan therapy. Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically results in a shorter life expectancy. However, the patient's heart failure was controlled by losartan, propranolol and other anti-congestive medications, which may have prolonged his survival.

Aortic root dilatation in patients with Alport’s syndrome

A total of 50 patients from 45 unrelated families diagnosed with Alport’s syndrome were examined. The diagnosis was based on molecular genetic testing or kidney biopsy. To assess changes in the aortic root, its volume was examined (calculation methods were given). Most patients with Alport’s syndrome were found to have cardiovascular disorders, such as hypertension; dilatation of the ring of the aortic valve; dilatation of the sinuses of Valsalva; some patients had dilatation of the sinotubular junction; dilatation of the ascending aorta; enlargement of the left ventricle; mitral and aortic insufficiency. In the patients with Alport’s syndrome, the median value of aortic root volume is 9.9 Z3, which substantially exceeds the permissible upper normal limit according to the general population data, which is 2.82 Z3. The rate of aortic root dilatation (volume increase) in the patients with Alport’s syndrome rises with an increase in the surface area of the body. In Alport’s syndrome, aortic root dilatation is unrelated to the presence of hypertension that occurs with a relative frequency of 0.52. Dilatation of the ascending aorta in Alport’s syndrome is diagnosed with a relative frequency of 0.37 and significantly more frequently diagnosed in male subjects (the statistical significance of a two-sided test is p=0.056; Fisher’s test is p=0.097; risk posed for men is OR = 7.2; 95% CI, 1.63-31.72. Changes in the cardiovascular system are also detected in female carriers of X-linked Alport’s syndrome; therefore they should be followed up by a cardiologist.

Invited Commentary

Invited Commentary

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model. Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent. Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.

Effect of Aortic Valve Replacement on Aortic Root Dilatation Rate in Patients With Bicuspid and Tricuspid Aortic Valves

It remains unclear whether aortic valve replacement (AVR) has an effect on the aortic root dilatation rate in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The present study evaluated the pre- and postoperative annual aortic root dilatation rates in BAV and TAV. A total of 93 patients (67 ± 11 years; 71% men) who underwent AVR between 2003 and 2013 and had at least 2 pre- and postoperative echocardiographic studies 1 year or more apart were included in this retrospective observational study. The sinus of Valsalva (SOV), sinotubular junction (STJ) and ascending aorta (AAo) were measured in the parasternal long-axis view. Patients with BAV (n= 22) were significantly younger and had less coronary artery disease than patients with TAV (n= 71). At all points in time, the aortic root diameters were larger in BAV compared with TAV. Preoperatively, the STJ and AAo grew significantly faster in BAV compared with TAV (STJ, 0.27versus 0.04 mm/y; p= 0.021; AAo, 0.42 versus 0.15mm/y; p= 0.019). After operation, there were no significant differences in aortic root dilatation rates between BAV and TAV (SOV, -0.01 versus 0.15 mm/y; p= 0.096; STJ, 0.08 versus 0.05 mm/y; p= 0.676; AAo, 0.28 versus 0.35 mm/y; p= 0.745). The annual aortic root dilatation rates were significantly higher in BAV compared with TAV before AVR. However, after AVR, aortic root dilatation rates were similar in BAV and TAV, suggesting an important role of hemodynamics on aortic root dilatation in BAV.

Aortic root dilatation rate in pediatric patients with Marfan syndrome treated with losartan

Medical therapy with angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and/or beta-blockers was reported to reduce aortic root dilatation rates in pediatric patients with Marfan syndrome. No data are available in the literature on losartan effects after 3 years of therapy. The aim of our study was to establish whether losartan reduces aortic root dilatation rates in pediatric patients with Marfan syndrome in the mid and long term. This is a retrospective analysis of 38 pediatric patients with Marfan syndrome followed at the Marfan Clinic of S. Orsola-Malpighi Hospital of the University of Bologna (Italy). Aortic diameters were measured at sinuses of Valsalva and proximal ascending aorta with transthoracic echocardiography. After a mean follow-up of 4.5 ± 2.5 years (range 2-9 years), aortic root z score at sinuses of Valsalva and proximal ascending aorta remained stable. The average annual rate of change in aortic root z score was -0.1 ± 0.4 and 0 ± 0.3 at sinuses of Valsalva and proximal ascending aorta, respectively. The mean dose of losartan was 0.7 ± 0.3 mg/kg/day. Three patients were non-responders, probably because of late beginning or low dose of therapy. Eight patients underwent cardiac surgery (aortic root surgery in 5 and mitral valve repair in 3), all of them started losartan later in life. Despite the retrospective design of the study and the small sample size, a beneficial effect of losartan therapy was observed in pediatric patients with Marfan syndrome in the mid and long term. Late beginning or low doses of losartan can turn off the effects of therapy.

Abstract 15146: Updated Meta-Analysis of Role of Angiotensin Blockade in Reducing Aortic Dilatation in Patients With Marfan Syndrome

Introduction: Patients with Marfan Syndrome have an increased risk of sudden death due to aortic dissection, mostly preceded by aortic dilatation.There has been considerable interest in evaluating the role of angiotensin blockade with Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARB) on reducing the progression of aortic root dilatation in these patients. While earlier studies showed considerable benefit with ACE/ARB, recently large scale Randomized Control Trials showed conflicting results. The purpose of this meta-analysis was to assess the role of angiotensin blockade in reducing the rate of aortic root dilatation in patients with Marfan Syndrome. Methods: We searched PubMed, EMBASE, and Cochrane Central Register of Clinical Trials from the inception to May 30, 2015 using the terms “Marfan syndrome”, “angiotensin converting enzyme inhibitors” and “angiotensin II-receptor blockers”. Data was extracted using standardized protocol.The main outcome of the present analysis was the change in aortic root diameter with ACE/ABR therapy compared to control. The random effects model of DerSimonian and Laird was used. The statistical analysis was done in line with recommendations from the Cochrane Collaboration using Review Manager (RevMan) version 5.3. Results: Six studies enrolling a total of 1252 patients were included in the final analysis. Five were randomized controlled trials and one was an observation study. Analysis showed that there was no significant benefit with ACE/ARB in reducing aortic root dilatation rate compared to control [Mean Difference of -0.24 ; 95 % CI -0.36 to -0.13, P < 0.00001]. Conclusion: Based on the results of this meta analysis which includes data from the most recent trials, there is no significant benefit with ACE/ARB treatment on reducing the rate of aortic root dilatation in patients with Marfan Syndrome.

Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement.

Aortic diameter is an imperfect predictor of aortic complications in connective tissue disorders (CTDs). Novel indicators of vascular phenotype severity such as aortic stiffness and vertebral tortuosity index have been proposed. We assessed the relation between aortic stiffness by cardiac MRI, surgical root replacement, and rates of aortic root dilation in children and young adults with CTDs. Retrospective analysis of cardiac MRI data on children and young adults with a CTD was performed to derive aortic stiffness measures (strain, distensibility, and β-stiffness index) at the aortic root, ascending aorta, and descending aorta. Vertebral tortuosity index was calculated as previously described. Rate of aortic root dilation before cardiac MRI was calculated as change in echocardiographic aortic root diameter z score per year. In 83 CTD patients (median age, 24 years; range, 1-55; 17% <18 years of age; 60% male), ascending aorta distensibility was reduced in comparison with published normative values: median z score, -1.93 (range, -8.7 to 1.3; P<0.0001 versus normals). Over a median follow-up period of 2.7 years, there were no aortic dissections or deaths, but 16 of 83 (19%) patients underwent surgical aortic root replacement. In multivariable analysis, lower aortic root strain (P=0.05) and higher vertebral tortuosity index (P=0.01) were independently associated with aortic root replacement. Lower ascending aorta strain (P=0.02) was associated with a higher rate of aortic root dilation. Higher aortic stiffness is associated with higher rates of surgical aortic replacement and aortic root dilation in children and young adults with CTDs.

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197). Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations. http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423.