{"paper_id":"0c24b31a-d08e-41c1-9827-cf4af76f997f","body_text":"Are aortic biomechanical properties early markers of dilatation in1\npatients with Marfan Syndrome? – A Systematic Review and2\nMeta-Analysis3\nClaire Rosnel 1, Raphael Sivera 2, Elena Cervi 3, Mark Danton 4,5, Silvia Schievano 2, Claudio4\nCapelli2, and Ankush Aggarwal 1,*\n5\n1Glasgow Computational Engineering Centre, James Watt School of Engineering, University of Glasgow, Glasgow, Scotland,6\nUK7\n2Institute of Cardiovascular Science, University College London, London, England, UK8\n3Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital for Children, NHS Foundation Trust, London,9\nEngland, UK10\n4Department of Paediatric Cardiac Services, Royal Hospital for Children, Glasgow, Scotland, UK11\n5School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow, Scotland, UK12\n*For correspondence, email: ankush.aggarwal@glasgow.ac.uk13\nAbstract14\nBackground: Although the stiffness of tissue is known to play an important role in aortic dilatation, the current15\nguidelines for offering a preventative aortic surgery in patients with Marfan syndrome rely solely on the aortic16\ndiameter. In this systematic review and meta-analysis, we analyze and compare literature on in-vivo aortic stiffness17\nmeasurements in Marfan patients. Our aim is to assess the potential of these measurements as early indicators of18\naortic dilatation.19\nMethods: Following the PRISMA guidelines, we collected literature on diameter and three in-vivo stiffness mea-20\nsures: Pulse Wave Velocity (PWV), β-stiffness index and Distensibility, at five different aortic locations in patients21\nwith Marfan syndrome. Reported results were reviewed and compared against each other. For meta-analysis, an22\naugmented dataset was created by combining extracted data from the reviewed literature. Regression with respect23\nto age and statistical comparison were performed on the augmented dataset for all three measures at five different24\nlocations.25\nResults: 30 articles reporting data from 1925 patients with Marfan and 836 patients without Marfan were reviewed.26\nPWV was found to be statistically higher in Marfan at most aortic locations, but only when the aorta is already27\ndilated. Distensibility was found to be lower at all aortic locations even in non-dilated aortas, and its decrease has28\nbeen associated with higher chances of developing aortic dilatation. β-stiffness index was higher in Marfan patients29\nand was positively correlated with the rate of aortic dilatation, emphasizing its role as a valuable indicator. In our30\nmeta-analysis based on a total 1197 datapoints, diameter was found to be higher only at the root (p < 0.001). All31\nstiffness measures showed a significant variation with age. PWV at the root and carotid-femoral region was not32\nstatistically different (p = 0.62 and p = 0.14 respectively), but was positively correlated with age at all locations.33\nDistensibility and β-stiffness index were different in Marfan patients at all locations, and the difference was more34\npronounced after accounting for age-related variation.35\nConclusion: Based on the results in the literature, β-stiffness index and distensibility emerge as the best predictors36\nof future aortic dilatation. Our meta-analysis quantifies age-related changes in aortic stiffness and highlights the37\nimportance of accounting for age in comparing these measurements. Missing diameter values in the literature limited38\nour analysis. Further analysis based on combined aortic stiffness and diameter criteria is recommended to evaluate39\naortic disease in a comprehensive way and assist clinical decisions for prophylactic surgery.40\nKeywords: Marfan syndrome; In-vivo stiffness; Aorta; Pulse wave velocity (PWV); Distensibility, β-stiffness index41\n1\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n1 Introduction42\nMarfan Syndrome (MFS) is a heritable connective tissue disorder caused by a mutation of the fibrillin-1 gene (FBN1).43\nThe FBN1 mutation increases the fragmentation of elastic fibers in the aortic media, leading to compromised strength44\nand structure of the tissue [1]. As a consequence, MFS exposes patients to higher risks of aortic diseases such as45\ndilatation, dissection and rupture due to stiffening of the vessel’s walls. 50% of undiagnosed and untreated MFS46\npatients die by the age of 40 due to cardiovascular complications [2]. Early diagnosis via cardiovascular imaging is47\nthus crucial for suspected Marfan patients, and close monitoring is essential for confirmed patients. Echocardiograms48\nand Magnetic resonance imaging (MRI) are examples of imaging procedures conducted to evaluate changes in aortic49\nsize and expansion rate. The current 2022 ACC/AHA clinical guidelines for preventive surgical intervention is50\nlargely based on the aortic root diameter with a threshold at 50mm, or 45mm in patients with increased risks of51\naortic dissection [3]. Surgery is also recommended when the cross-sectional aortic root area to patient height ratio52\nis greater than 10 cm 2/m. However, dissection and rupture are known to occur below these thresholds [4, 5, 6], and53\ndiameter alone may not fully account for the biomechanical properties of aortic tissue, which are expected to play54\nan important role in aneurysm progression and adverse events. While only diameter is currently used to predict55\nrisks of dissection and rupture, aortic stiffness emerges as a predictor of aortic dilatation, offering insights into the56\nprobability of adverse events.57\nConsiderable research has focused on investigating how biomechanical properties of the aorta can be early predic-58\ntors of dilatation using in-vivo measures of aortic stiffness, namely 1) pulse wave velocity (PWV), 2) distensibility,59\nand 3) β-stiffness index. Although some results have shown that aortic stiffness measured in-vivo may perform60\nbetter than diameter assessment to predict aneurysmal growth, no consensus has been established on what stiffness61\nindicator to use, which aortic segment to consider, how it differs from healthy patients, and how the differences evolve62\nwith age.63\nThis systematic review of the literature therefore aims at gathering published research studies that report aortic64\nstiffness using PWV, distensibility and β-stiffness index in patients with Marfan syndrome and healthy patients.65\nA comprehensive analysis of their correlation with age, and their potential as early indicators of aortic dilatation66\nis conducted. In addition, to overcome variations in individual studies, we aim to create a larger, consolidated67\ndataset from the selected studies and perform a meta-analysis to determine age- and disease-related variations and68\ndifferences.69\n2 Methods70\nThe following systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analyses71\n(PRISMA) recommendations and guidance [7]. In this section, the eligibility and search criteria necessary for the72\nidentification and selection of relevant published studies are defined. The data extraction and augmentation process,73\nas well as the statistical techniques used to conduct the meta-analysis are also described.74\n2.1 Inclusion criteria, information sources and search strategy75\nStudies focusing on one or more of the three clinically established aortic stiffness measures - PWV, distensibility and76\nβ-stiffness index - were selected for patients diagnosed with MFS. Regarding the diagnosis of MFS, the revised Ghent77\ncriteria is the most widely accepted since its proposition in 1996 [8]. Therefore, only the studies published between78\n1996 and September 2022 were included. Cohort studies, cross-sectional studies, case-control studies, and case series79\nwere considered, whereas conference abstracts, book chapters, case reports, reviews, editorials, expert opinions and80\nletters were excluded. The review focused on early signs of dilatation, and thus excluded papers investigating severe81\ncomplications such as dissection and rupture. Articles focusing on the following aspects were also excluded: effect of82\nmedication on aortic stiffness, ex-vivo mechanical characterization, cellular scale investigations, and effect of aortic83\ncurvature on its mechanical behavior. Additionally, the review was restricted to publications in the English language.84\nTwo electronic databases, PubMed and ScienceDirect, were screened to find publications based on the inclusion85\ncriteria. A time filter was applied to encompass research published between 1996 and September 2022. Between May86\n2022 and September 2022, the databases were searched using the following MeSH terms: ‘Aortic’ AND ‘Stiffness’87\nAND ‘Marfan’,88\n2\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\n2.2 Clinical metrics of aortic stiffness89\nStiffness refers to the ability of a material to withstand deformation under an applied force. The in-vivo stiffness of90\narteries is influenced by their geometry and the biomechanical properties of the tissue. In this section, we define the91\nthree in-vivo parameters that are used in this review to quantify aortic stiffness.92\n■ PWV is defined as the speed of the pressure waveform over a designated portion of a vessel. Higher PWV\nvalues indicate a wave that travels faster along the arterial segment, generally a consequence of stiffer tissue.\nThe wave is detected using pressure transducers or Doppler echocardiography, and its travel time, called transit\ntime, is measured by estimating the time of travel of the foot of the wave over a known arterial distance. The\npulse wave velocity is therefore calculated as the distance between two chosen points divided by the transit\ntime,\nPWV = Distance\nTransit time. (1)\n■ Distensibility (Dist) is directly calculated on in-vivo images. It is defined as the relative change in a vessel’s lu-\nminal area for a unit pressure increment. Thus, a lower distensibility value indicates stiffer tissue. From in-vivo\nimages, the arterial luminal area at systole and diastole, denoted as As and Ad respectively, are measured at a\nchosen location. Pressure measurements are commonly taken at the brachial artery using a sphygmomanome-\nter cuff, where the systolic pressure (denoted as Ps) and diastolic pressure (denoted as Pd) are measured.\nDistensibility is thus calculated as\nDist = As − Ad\nAd(Ps − Pd) . (2)\n■ The β-stiffness index ( β-SI) is also derived from in-vivo image-based measurements. Higher values indicate\na stiffer tissue, i.e., β-SI is inversely correlated to the distensibility. β-SI is defined as the logarithm of the\npressure ratio to relative change in diameter, and is dimensionless. The diameter in systole and diastole is\nmeasured on cross-sectional views of the aorta, and pressure using sphygmomanometer cuff. β-SI is calculated\nas\nβ-SI = ln\n\u0012 Ps\nPd\n\u0013 Dd\nDd − Ds\n, (3)\nwhere Ps, Pd, Ds and Dd are the systolic pressure, diastolic pressure, systolic diameter and diastolic diameter,93\nrespectively.94\n2.3 Data collection process95\nThe details of the selected papers and their full-text manuscripts were stored in a reference management software96\n(Zotero). Information from these manuscripts was extracted, capturing the following data: publication details, overall97\naim of the study, study design (prospective, retrospective, multicenter, or longitudinal), cohorts’ size, cohorts’ mean98\nage, imaging modality (Echocardiography (Echo) or Magnetic Resonance Imaging (MRI)), presence of diagnosed99\naneurysms in the cohort, and the aortic stiffness measure reported at five aortic locations: aortic root, ascending100\naorta (Aao), aortic arch (Arch), descending aorta (Dao), and carotid-femoral (only for PWV).101\nDiscrepancies in results from the literature may be attributed to the specificity of the cohorts included in each102\nindividual paper, particularly factors like age and population size. Additionally, statistical tests conducted on their103\nsampled cohorts might not be fully representative of the broader population. A meta-analysis was therefore sought104\non the following quantities of interest: PWV, distensibility, β-stiffness index, diameter, and age. The aim was105\nto perform a comprehensive statistical analysis by treating the collective results from the literature as one unified106\ndataset, and offering deeper insights than what can be derived from individual papers. The unified dataset creation107\nrequired extraction of data points from selected manuscripts, but with the following exclusion criteria. For studies108\ninvestigating several connective tissue disorders, measurements were excluded from the meta-analysis if Marfan data109\npoints could not be separated from others. Since the focus of this analysis is on the native biomechanical properties110\nwithout any effects of surgical intervention, measurements were also rejected if results from patients who underwent111\nan aortic surgical procedure (e.g., PEARS, Bentall procedure) were not separable from the rest of the Marfan cohort.112\nHowever, data points with unknown surgical status were included under the assumption that if surgery was performed,113\nit would be explicitly mentioned in the respective articles. Patients under medication were included since that they114\nrepresent a large portion of the diagnosed Marfan population. When studies presented data separately for aneurysmal115\n3\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nPWV Distance\nTransit time\n1√ρDist\nr\n(Ps−Pd)β-SI\n2ρ ln\n\u0010\nPs\nPd\n\u0011\nDistensibility\n(Dist)\n1\nρP W V 2\nAs−Ad\nAd(Ps−Pd)\n2 ln\n\u0010\nPs\nPd\n\u0011\n(Ps−Pd)β-SI\nβ-stiffness index\n(β-SI)\n2ρ ln\n\u0010\nPs\nPd\n\u0011\nP W V 2\n(Ps−Pd)\n2 ln\n\u0010\nPs\nPd\n\u0011\n(Ps−Pd)Dist ln\n\u0010\nPs\nPd\n\u0011\nDd\nDd−Ds\nTable 1: Calculation equations (in gray cells) and conversion equations (in white cells) for the three aortic stiffness\nmeasures\nand non-aneurysmal Marfan aortas, only the non-aneurysmal measurement was selected. For longitudinal studies116\nwith several time points reported, only the baseline measurement was extracted. Finally, in papers where results117\nwere reported per age range, the mean was calculated and collected. For articles where individual participant data118\npoints were available, they were digitized directly from plots in the manuscript using WebPlotDigitizer [9]. In cases119\nwhere such individual data points were not provided, mean and standard deviation (SD) or median and interquartile120\nranges (IQR) were manually extracted for each quantity.121\n2.4 Data augmentation process122\nIn the literature, various image-based aortic stiffness measures are employed to characterize the mechanics of vascular123\nwalls. However, the measures often use different units, leading to inconsistency and lack of standardization, as124\npreviously pointed out by Alhalimi et al. [10]. To address this issue, our data augmentation process involved125\nemploying standardized formulae and units, as well as conversion equations to transform one aortic stiffness index126\ninto another. Specifically, distensibility can be converted into β-SI using the relative change in area ( As − Ad)/Ad =127\n(D2\ns − D2\nd)/D2\nd ≈ 2(Ds − Dd)/Dd where As, Ad, Ds, Dd are systolic area, diastolic area, diameter in systole and128\ndiameter in diastole respectively. The conversion of PWV to image-based aortic stiffness measures can be achieved129\nusing the Bramwell-Hill equation [11]. The conversion formulae are summarized in Table 1, where ρ is the blood130\ndensity approximated to be 1059 kg/m3. Mean values of systolic ( Ps) and diastolic pressure (P d) reported in the131\narticles were used for the calculations. It is worth noting that in cases where only the pulse pressure ( Ps − Pd) was132\nreported instead of systolic and diastolic pressures individually, the β-stiffness index could not be calculated.133\nIn instances where individual data points were not reported, mean and standard deviation of the quantity were\nused. However, as noted by Weir et al. [12], when results exhibit a skewed distribution, researchers often report the\nmedian and interquartile ranges instead of the mean and variance information. To ensure that such cases were not\nexcluded from the analysis, missing mean and standard deviation values were calculated from the provided median\nand interquartiles using Wan et al.’s method [13], described as follows. The mean ˜ x can be estimated from median\nand interquartiles as\n˜x ≈ q1 + m + q3\n3 , (4)\nwhere q1 and q3 represent the first and third interquartiles, and m denotes the median. The standard deviation SD\nis estimated as\nSD = q3 − q1\n2Φ−1\n\u0010\n0.75n−0.125\nn+0.25\n\u0011 , (5)\nwhere Φ is the cumulative distribution function of a standard normal distribution and n is the size of the cohort.134\nTo summarise, the augmented dataset on which the meta-analysis is conducted consisted of three types of data:135\n(i) Individual patients’ data points that were directly digitized and collected from plots in the manuscripts.136\n(ii) Mean and standard deviation values collected from the manuscripts.137\n4\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\n(iii) Mean and standard deviation values calculated from the median and interquartiles reported in manuscripts138\nusing Wan et al.’s method [13].139\n(iv) Calculated values, which were generated using the conversion equations from Table 1 to transform one reported140\naortic stiffness measure into another.141\n2.5 Statistical analysis142\nIn the meta-analysis, comparison tests between Marfan and control and linear regressions with age were performed\non the augmented dataset. As stated previously, the dataset is composed of individual datapoints as well as mean\nand standard deviation values. In order to run statistical tests, all values were expressed as mean and SD, such that\nthe overall means for the Marfan ( i = M) and control ( i = C) cohorts are calculated as\nXi =\nP(µjnj)P nj\n(6)\nwhere µj and nj are the mean and size of the cohort in paper j, and the corrected sample standard deviations are\ncalculated as\nsi = 1P nj − 1\n\u0014X\n((nj − 1)σ2\nj + nj(µj − Xi)2)\n\u0015\n(7)\nwhere σj is the standard deviation in paper j.143\nMarfan and control were compared using the Welch test, which examines the null hypothesis that two populations144\nhave equivalent means. This test is favored over the Student’s t-test when the two samples have unequal variances.145\nBonferroni correction was applied to account for multiple comparisons type two error.146\nTo better understand the independent effect of Marfan syndrome on distensibility, PWV or β-SI and to account147\nfor age-related effects, linear regressions and projections at age-zero were conducted. To perform the regressions, the148\nnormality of the dataset was tested using Shapiro–Wilk test. Due to the lack of consistent normality in the initial149\ndata distribution, a logarithmic transformation was applied to the dataset. The association between variables and age150\nwere evaluated using the coefficient of determination (R2). The slope of the linear regression enables us to determine151\nif age-related changes occur at a faster rate in Marfan patients. To investigate whether Marfan patients are born with152\naltered stiffness or if it changes over time, log-values of the three aortic stiffness measures were projected at age-zero153\nusing the linear regression. Welch comparison tests were then run on the projected values. The projection allowed154\nus to discern whether statistical differences between the two groups can be found once the age-related variations had155\nbeen factored out. In all statistical tests, significance was considered at a p-value less than 0.05. All analyses were156\nperformed using Python and the Scipy library.157\n3 Results158\n3.1 Search results159\nThe flowchart in Figure 1 illustrates the paper selection process following PRISMA guidelines. Initially, 639 published160\narticles were identified, comprising 76 papers from PubMed, 553 from Science Direct, and 10 from reference list hand-161\nsearching. After removing duplicates, 616 papers remained, which were then assessed against exclusion/inclusion162\ncriteria by examining the title and abstract only. Among them, 572 articles were excluded, primarily for being163\nunrelated to in-vivo measures of aortic stiffness in Marfan diagnosed patients, or for focusing on blood flow patterns.164\nSubsequently, 44 texts were read fully, and 14 were rejected for either not using the revised Ghent criteria for MFS165\ndiagnosis [8] or for merging Marfan patients with other tissue disorders. Finally, a total of 30 papers were selected166\nbased on the eligibility criteria and search strategy mentioned in Methods section. For the meta analysis, 6 of the167\n30 articles were excluded for not reporting Marfan data separately from others.168\n3.2 Characteristics of included studies169\nThe review of the literature offered valuable insights into the assessment of stiffness in patients with Marfan Syndrome,170\nas it encompassed studies from diverse sources published over a span of 20 years in ten different countries. Out of171\nthe 30 selected studies, 16 were longitudinal, providing crucial information on how stiffness evolves with age. The172\n5\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nStudies identified through \nelectronic database search\nPubMed (n = 76)\nScience Direct (n = 553)\nIdentification\nReferences identified through \nhand-search of reference lists\n(n = 10)\nScreening\nDuplicate records removed \n(n = 23)\nRecords screened (title ± abstract) \n(n = 616)\nIncluded\nRecords excluded (n = 572)\n▪Unrelated to in-vivo \nmeasures of aortic stiffness\n▪Focus on blood flow patterns\nFull-text assessed for eligibility\n(n = 44)\nReports not retrieved \n(n = 14)\n▪Do not use the revised Ghent \ncriteria for Marfan diagnosis\n▪ Marfan syndrome is not \nseparated from other \nconnective tissue disorders\nReports excluded from meta-\nanalysis (n = 6)\n▪Quantitative data does not \nseparate Marfan from other \ncohorts\nStudies included in the literature \nreview\n(n = 30)\nStudies included in the meta-\nanalysis (n = 24)\nFigure 1: The flow diagram presents the process of inclusion given the eligibility criteria using the PRISMA 2020\nguidelines\n6\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nremaining 14 were case-control studies, allowing for a quantification of the differences in stiffness properties between173\nindividuals with and without Marfan Syndrome.174\nOf the selected papers, 17 used echocardiography to monitor the size of the aorta and to calculate stiffness175\nmeasures at various aortic locations, while 13 employed MRI. Only one study by Prakash et al. [14] utilized both176\nimaging modalities: MRI for distensibility and β-SI calculation and echocardiography for monitoring the aortic size.177\nTable 2 provides a comprehensive overview of the included papers in the qualitative synthesis, along with their178\nrespective main characteristics.179\nTable 2: Main characteristics of the 30 studies included in the systematic review and meta-analysis\nAuthor Country\nMarfan\ncohort:\nsize\n(mean\nage)\nControl\ncohort:\nsize\n(mean\nage)\nImaging\nmodality\nIncluded\nin the\nmeta-\nanalysis?\nQuantity reported\nGroenink et al. [15] Netherlands 78 (31) 23 (28) MRI Yes PWV, Distensibil-\nity\nSandor et al. [16] Canada 14 (15.7) 6 (12.3) Echo Yes PWV, β-SI\nNollen et al. [17] Netherlands 78 (31) - MRI Yes PWV, Distensibil-\nity\nBaumgartner et al.\n[18]\nAustria 19 (17.7) 19 (17.7) Echo Yes Distensibility, β-SI\nOosterhof et al. [19] Netherlands 78 (31) 17 (44) MRI Yes PWV\nBradley et al. [20] Canada 26\n(13.14)\n69\n(13.14)\nEcho Yes PWV, β-SI\nVitarelli et al. [21] Italy 31 (26) 21 (26) Echo Yes PWV, Distensibil-\nity, β-SI\nBaumgartner et al.\n[22] Austria 46 (17.4) 46 (17.6) Echo Yes Distensbility, β\nFattori et al. [23] Italy 20 (27.8) 14 (29) MRI Yes Distensibility\nMortensen et al.\n[24]\nGermany 50 (32) - Echo Yes PWV\nKiotsekoglou et al.\n[25] U.K 31 (31) 31 (33) Echo Yes PWV, β-SI\nWestenberg et al.\n[26]\nNetherlands 25 (36) 25 (36) MRI Yes PWV\nWit et al. [27] Australia 55 (40.5) 69\n(41.35) Echo Yes PWV, distensibil-\nity, β-SI\nKr¨ oner et al. [28] Netherlands 21 (36) 26 (30) MRI Yes PWV\nTeixido-Tura et al.\n[29] Spain 80 (32) 36 (35.2) MRI Yes PWV, Distensibil-\nity\nPrakash et al. [14] U.S 45 (27) - Echo,\nMRI No Distensibility, β-SI\nAkazawa et al. [30] Japan 26 (15) - Echo No Distensibility, β-SI\nSingh et al. [31] U.S 15 (36.9) 10 (42.9) MRI No β-SI\nMerlocco et al. [32] U.S 26\n(25.11) - MRI No Distensibility, β-SI\n7\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nGrillo et al. [33] Italy 51 (12) 80 (11.9) Echo Yes PWV\nSalvi et al. [34] Italy 116\n(33.7) - Echo Yes PWV\nSelamet Tierney\net al. [35]\nU.S 608\n(11.2)\n- Echo No Distensibility, β-SI\nSch¨ afer et al. [36] U.S 20 (18) 22 (15) MRI Yes PWV, Distensbility\nGuala et al. [37] Spain 117\n(25.3)\n- MRI Yes Distensibility\nYan et al. [38] Germany 69\n(34.43)\n90\n(67.27) Echo Yes Distensibility, β-SI\nGuala et al. [39] Spain 44\n(36.95)\n36\n(39.40)\nMRI Yes PWV, Distensibil-\nity\nCui et al. [40] Canada 49 (17.9) 87\n(18.20) Echo Yes PWV, β-SI\nAndel et al. [41] Netherlands 35 (28) - MRI Yes Distensibility\nWeismann et al.\n[42] Sweden 20 (22) 67 (25) Echo Yes PWV, Distensibil-\nity, β-SI\nCox et al. [43] U.S 32 (21.1) - Echo Yes Distensibility, β-SI\nIn total, the review included data from 1925 patients with MFS and 836 patients without MFS, treated as180\ncontrols, with mean age of participants ranging from 2 to 90 years old. A considerable fraction of the papers (10181\nout of 30) exclusively reported data for the Marfan cohort and did not include control data. As shown on Figure 2,182\ndiameter was primarily reported at the root and ascending aorta, with only about a third of the studies comparing183\nMarfan and control groups. In contrast, PWV was predominantly reported in the ascending part of the aorta, with184\nonly one study that considered controls in the descending aorta (Dao) and another in the abdominal aorta (Abao).185\nDistensibility was mostly reported in the ascending aorta, but only about a third of the papers included control data186\nfor comparison. The β-stiffness index was mainly reported in the root and ascending aorta.187\nIn Figure 3, the size of the Marfan cohort is depicted in relation to their age. The horizontal bars displayed188\nrepresent mean ± SD for each paper. Most of the articles encompassed cohorts with less than 60 patients, with age189\nranges spanning from pediatrics to 50 years old. Only three studies exceeded 100 participants and none of them190\nincluded controls in their analysis.191\n3.3 Main findings from the selected papers192\n3.3.1 Aortic diameter is the standard measure to compare Marfan and control193\nAmong the 30 selected papers, 14 compared the diameter at the root between Marfan and control cohorts, 14 at194\nthe ascending aorta, and 3 at the descending aorta. Table 3 summarizes the results of these comparisons. The195\nfindings from these studies indicated significant differences in aortic size between the two groups. Notably, all papers196\nreported a larger aortic root in Marfan patients, irrespective of the age of the cohort or correction for Body-Surface-197\nArea (BSA). 10 studies found that the ascending aorta (Aao) was larger in Marfan patients, and 5 studies found no198\nstatistical difference in the diameters of the descending aorta (Dao).199\n3.3.2 PWV is higher in Marfan patients, but only with dilated aortas200\nAmong the selected studies, 7 compared PWV at the Aao between Marfan and control cohorts, 8 examined PWV201\nat the arch, 7 in the descending aorta, and 5 from carotid to femoral (Table 3). Consistently, a significantly higher202\nPWV was observed in all aortic regions from proximal to distal, as well as from carotid to femoral, in MFS patients.203\nThese differences remained valid even after adjusting for age and diameter. This finding highlights the presence of204\nincreased aortic stiffness in MFS patients across various regions of the aorta. However, in Oosterhof et al. [19] study,205\nafter correcting for age and diameter for the ascending aorta, no significant difference in PWV was observed between206\nadult patients with and without Marfan Syndrome.207\n8\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nNumber of articles\n23\n20\n2\n12\n7\n1\n4\n7\n9\n6\n8\n9\n15\n2\n9\n3\n9\n10\n1\n5\n2\n7\n4\n0\n2\n1\n0 0 0\n1 1\n3\n4 4\n1\n2 2\n3\n2\n0 0\n1\n0\n5\n10\n15\n20\n25\n30\nRoot\nAscending\nArch\nDescending\nAbdominal\nRoot\nAao\nArch\nDao\nAbao\nCarotid-femoral\nRoot\nAscending\nArch\nDescending\nAbdominal\nRoot\nAscending\nArch\nDescending\nAbdominal\nDiameter PWV Distensibility βstiffness index\nOnly Marfan values are reported\nMarfan and control values are \nreported and compared\nFigure 2: Number of articles reporting diameter, PWV, distensibility and β stiffness index at various locations. Black\nbars represent papers reporting only Marfan data, and gray bars represent papers including a control cohort and\ncomparing results to Marfan.\n9\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nFigure 3: Mean age and standard deviation of the Marfan cohort in selected articles, organized by\ncohort size. The histogram on the top illustrates the number of articles containing patients within\nspecific age ranges. The histogram on the right depicts the number of articles containing specific\ncohort sizes. One study (Selamet Tierney et al. [35]) is not included in this plot and consists of 608\nMFS patients with a mean age of 11.2 and a standard deviation of 6.3.\n10\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nDiameter PWV Distensibilit\ny β stiffness\nindex\nComparison\nb\netween\nMarfan and\ncontrol\nRo\not Aao Dao Aao Arc\nh Dao Carotid-\nfemoral Ro\not Aao Dao Ro\not Aao Dao\nStatistically\ndifferen\nt\n[15]∗\n[20]∗\n[16]\n[18]∗\n[22]∗\n[19]\n[25]∗\n[29]\n[21]∗\n[27]∗\n[14]∗\n[38]∗\n[40]\n[42]\n[16]\n[18]∗\n[22]∗\n[19]\n[25]\n[29]\n[21]∗\n[36]\n[38]∗\n[42]\n[29]\n[21]∗\n[36]\n[15]\n[26]\n[15]\n[19]\n[16]\n[20]\n[26]\n[28]\n[29]\n[36]\n[15]\n[19]\n[26]\n[28]\n[15]\n[26]\n[28] [34] [30]\n[23]\n[36]\n[32]\n[15]\n[29]∗\n[21]\n[32]\n[21]\n[29]∗\n[27]\n[16]\n[20]⋄\n[18]\n[22]\n[21]\n[25]\n[40]\n[18]\n[22]\n[21]\n[31]\nOnly\nstatistically\ndifferen\nt when\nthe aorta is\nalready dilated\n[21]\n[39] [21] [29] [30] [30] [30]\nNot\nstatistically\ndifferen\nt\n[15]∗\n[20]\n[26]∗\n[23]∗\n[15]∗\n[18]∗\n[22]∗\n[19]\n[31]\n[19]•\n[28]\n[36]\n[29]\n[36]\n[32] [30] [27]\nTable 3: Studies comparing diameter, PWV, distensibility and β-SI between Marfan and control, and\nresults of the statistical tests at different aortic locations.\nThe symbol ⋆ indicates quantities corrected for age, pulse pressure and diastolic area, ⋄ indicates that\nβ-SI is corrected for sex, height and age, and • indicates that PWV is corrected for age and diameter.\n11\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nAdditionally, in the studies conducted by Vitarelli et al. [21], Teixido-Tura et al. [29], and Guala et al. [39], it208\nwas observed that when separating the cohorts into dilated aortas and normal diameters, Marfan patients exhibited209\nincreased PWV compared to controls. However, this difference was significant only for already dilated aortas.210\nAccording to Teixido-Tura et al. [29], compared with distensibility, PWV demonstrated a slower decrease at the211\nearly stage of aortic dilatation. This suggests that PWV might not be as sensitive to changes in aortic biomechanics212\nduring the initial stages of aortic dilatation compared to distensibility. However, as the aortic dilatation progresses,213\nPWV gradually increases and eventually becomes significantly different between Marfan and control cohorts, but214\nonly when the aorta is already dilated.215\n3.3.3 Aortic distensibility is lower in Marfan patients216\nAmong the selected papers, 2 studies compared the distensibility at the root between Marfan and control cohorts,217\n7 studies examined the distensibility at the Aao, and 3 at the Dao (Table 3). Statistically lower distensibility was218\nconsistently reported in the aortic root, Aao, and Dao for Marfan patients. Furthermore, distensibility showed a219\nsignificant decrease with age: Groenink et al. [15] highlighted that, compared to juvenile Marfan cohorts in the220\nliterature, the mean distensibility was nearly half in adult patients. Distensibility appears to be an early marker of221\nbiomechanical changes in Marfan Syndrome. In Akazawa et al. [30]’s study on children, a difference in distensibility222\nof the root was observed between Marfan and control groups, even in non-dilated roots, at an early stage of life. In223\nthe Dao, distensibility did not differ whether the aorta was dilated or not.224\nFinally, studies conducted by Teixido-Tura et al. [29] and Vitarelli et al. [21] on older cohorts also reported lower225\ndistensibility in adult Marfan patients, whether their aortic root, ascending, or descending aortas were dilated or226\nnon-dilated. These results indicate a decrease in distensibility starting from the proximal aorta.227\n3.3.4 β-stiffness index is higher in Marfan patients228\nAmong the selected studies, 2 compared the β-SI at the root between Marfan and control cohorts, 8 examined the229\nβ-SI at the Aao, and 4 at the Dao (Table 3). The findings consistently revealed that the β-SI was significantly higher230\nin the root, Aao, and Dao in the MFS group when compared to control patients, even after adjusting for factors231\nsuch as sex, age, and height. Notably, unlike PWV, MFS patients demonstrated higher β-SI values than controls in232\nboth cases of aortic dilatation and normal aortic diameters. However, it is essential to consider the observation by233\nWit et al. [27] that, after 40 years of age, the β-SI did not show significant differences between Marfan and control234\ncohorts. This may have implications in understanding the progression of stiffness changes associated with age in235\nMarfan Syndrome patients.236\n3.3.5 Biomechanical stiffness measures can be early predictors of aortic dilatation237\nIn the 17 longitudinal studies, Marfan patients were followed at various time points throughout their lives, and the238\nevolution of stiffness parameters was measured. Statistical tests could identify a potential trend in the parameters’239\nevolution with age. The predictive power of each parameters was thus assessed with regards to aortic dilatation.240\nPWV241\nIn the study conducted by Groenink et al. [15], PWV was strongly correlated with age in control subjects at all levels242\nof the aorta. However, in MFS patients, the increase in PWV with age was significantly higher in the proximal aorta243\ncompared to healthy subjects, supporting the hypothesis of media degradation starting at the root [34]. Despite244\nits correlation with age, PWV was not found to be associated with progressive aortic dilatation at any level in the245\nlongitudinal study by Nollen et al. [17]. This suggests that PWV may not be a reliable candidate for predicting246\nfuture aortic dilatation in MFS patients. Furthermore, in patients with aortic root replacement, even though the247\ndistensibility of the graft was significantly lower than the distensibility of the native aorta, the PWV showed no248\ndifferences [17]. This indicates that PWV, as a regional measure, may not adequately differentiate diseased tissue249\nlocally and may be insensitive to differences in tissue composition.250\nA noteworthy exception is that PWV demonstrated high specificity and low sensitivity for predicting the absence251\nof regional dilatation in MFS patients in the longitudinal study by Kr¨ oner et al. [28]. Specifically, at least 78% of MFS252\npatients who showed no aortic growth at follow-up did not have increased regional PWV at baseline. Conversely,253\nless than 33% of patients who presented with increased PWV at baseline had increased aortic growth at follow-up.254\n12\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nDistensibility255\nSeveral studies, including Baumgartner et al. [18], Akazawa et al. [30], and Sch¨ afer et al. [36], have demonstrated256\nthat distensibility can serve as a diagnostic parameter in addition to the current diameter measurements. The257\nmain reason is that distensibility was found to be lower even in patients with normal diameters at the root and258\nascending aorta. In a longitudinal study by Baumgartner et al. [22], the probability of developing an aneurysm259\nwas calculated based on ascending aortic distensibility. The findings revealed that higher distensibility measured at260\nbaseline was associated with a lower probability of developing aortic dilatation at follow-up. Similarly, Nollen et al.261\n[17] demonstrated that distensibility was predictive of progressive descending thoracic aortic dilatation. A reduction262\nof one unit in distensibility was associated with a 4-fold increase in the risk of dilatation, independent of aortic263\ndiameter. However, distensibility was not found to be a significant predictor of dilatation at other aortic locations,264\nas noted by Teixido-Tura et al. [29]. This might be attributed to the relatively advanced stage of aortic disease in265\nthat particular study group. Additionally, Merlocco et al. [32] found a linear correlation between distensibility and266\nage, with a slightly higher decline with age compared to normal subjects.267\nβ-stiffness index268\nThe study by Cox et al. [43] provided important insights into the relationship between theβ-stiffness index and aortic269\ndilatation in Marfan patients. Their findings revealed that the β-stiffness index in the aortic root was positively270\ncorrelated with the dilatation rate, indicating that higher β stiffness values were associated with a faster rate of271\naortic dilatation. Interestingly, the baseline aortic root dimension alone did not show a significant correlation with272\nthe dilatation rate. This highlights the potential of the β-stiffness index as an independent and predictive measure273\nfor assessing aortic dilatation in Marfan patients.274\nAdditionally, the β-stiffness index was the least dependant on blood pressure variation, making it a robust275\nindicator of aortic stiffness, in comparison to distensibility [44]. Indeed, in Wada et al. [45] study on 7 subjects, no276\ncorrelation was found between β-stiffness index and mean blood pressure. In Sugawara et al. [46] study, β-stiffness277\nindex did not change significantly after decreasing the blood pressure using α-adrenergic blockade.278\n3.4 Meta analysis279\n3.4.1 Analysis of the augmented dataset280\nThrough the data extraction and augmentation process, the dataset included 286 data points for diameter, 1063281\nfor PWV, 1063 for distensibility, and 733 for the β-stiffness index. Out of these, 1278 data points were associated282\nwith a corresponding age value: 1027 age points had corresponding PWV, distensibility and β-SI, 194 only had283\ncorresponding PWV and distensibility, and 57 only had corresponding diameter. Original data points constituted284\n36% of the entire dataset, with the remaining being part of the augmentation process. Specifically for diameter, 62285\ndata points were mean values with 11 converted using Eqs. 4 and 5, and 222 individual points were extracted from286\nmanuscripts using WebPlotDigitizer. For PWV, 464 points were calculated using conversion formulas, 39 points were287\nmean values with 8 using Eqs. 4 and 5, and 544 individual data points were from the manuscripts. As for distensibility,288\n839 points were calculated using conversion formulas, 20 points were mean values with 9 using Eqs. 4 and 5, and 188289\nwere individual data points. Lastly, for the β-stiffness index, 579 points were calculated using conversion formulas,290\n24 were mean values with 6 using Eqs. 4 and 5, and 238 were individual data points.291\nOut of the 1172 data points in the augmented dataset, the majority (1082) were associated with patients who292\ndid not undergo surgery, 90 data points were unknown (not specified in the article). Regarding medication, 139 data293\npoints were from patients under medication such as beta-blockers, 866 data points were from patients not under294\nmedication, and 167 data points were unknown (not specified in the article). Table 4 summarizes the number of data295\npoints in the augmented dataset obtained from each article.296\n3.4.2 Comparison tests between Marfan and control on the augmented dataset297\nConsistent with previous literature findings, diameter was indeed statistically larger in Marfan patients at the Root298\n(Figure 4), but no difference in the Aao and Dao was detected. Specifically, the mean diameter in the Marfan cohort299\nwas 3.91cm at the root, 2.98cm at the Aao, and 2.10cm in the Dao, compared to 3.05cm, 3.00cm, and 1.86cm,300\nrespectively, for the control cohort. Distensibility was significantly lower in Marfan patients except at the root after301\nBonferroni correction with mean values (in 10−3mmHg−1) of 2.46 in the Root, 3.57 in the Aao, 6.18 in the Arch, and302\n4.23 in the Dao, compared to 2.99 6.11 , 8.17 , and 6.56, respectively, for controls (Fig. 5). The β-SI was also higher303\n13\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nPapers Number of datapoints\nWit et al. [27] 244\nWestenberg et al. [26] 149\nCui et al. [40] 134\nTeixido-Tura et al. [29] 127\nGroenink et al. [15] 109\nOosterhof et al. [19] 101\nBaumgartner et al. [18] 95\nWeismann et al. [42] 67\nSch¨ afer et al. [36] 27\nFattori et al. [23] 19\nBaumgartner et al. [22] 14\nKiotsekoglou et al. [25] 8\nVitarelli et al. [21] 8\nBradley et al. [20] 8\nGuala et al. [47] 8\nYan et al. [38] 8\nSandor et al. [16] 6\nKr¨ oner et al. [28] 5\nAndel et al. [41] 5\nNollen et al. [17] 5\nSalvi et al. [34] 4\nMortensen et al. [24] 4\nGrillo et al. [33] 4\nGuala et al. [37] 2\nCox et al. [43] 1\nTable 4: Papers included the meta-analysis and the number of datapoints in the augmented dataset\n14\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nFigure 4: Mean and SD of aortic diameters in Marfan and control cohorts at three different locations\nshow a signficant difference only at the root.\nin Marfan patients at all locations, with mean values of 13.93 in the root, 5.97 in the Aao, 4.42 in the Arch, and304\n6.53 in the Dao, compared to 8.25, 3.64, 3.36, and 4.90, respectively, for the control cohort (Fig. 5). Interestingly,305\nno statistically different PWV was found in the Root and from carotid to femoral (Fig. 5). Table 5 summarizes the306\nresults of the statistical tests.307\nRo\not Aao Arc\nh Dao Carotid-femoral\nDiameter\nAll\nages\ncombined:\np = 7.89 × 10−9\nAll\nages\ncombined:\np = 0.86\nAll\nages\ncombined:\np = 0.15\nPWV\nAll\nages\ncombined:\np = 0.62\nAge-zero\nprojection:\np = 0.30\nAll\nages\ncombined:\np = 0.0025\nAge-zero\nprojection::\np = 0.0020\nAll\nages\ncombined:\np = 3.30 × 10−5\nAge-zero\nprojection:\np = 3.25 × 10−9\nAll\nages\ncombined:\np = 1.57 × 10−6\nAge-zero\nprojection:\n2.92 × 10−14\nAll\nages\ncombined:\np = 0.14\nAge-zero\nprojection:\np = 0.65\nDistensibilit\ny\nAll\nages\ncombined:\np = 0.015\nAge-zero\nprojection:\np = 1.15 × 10−17\nAll\nages\ncombined:\np = 8.36 × 10−13\nAge-zero\nprojection:\np = 0.0020\nAll\nages\ncombined:\np = 0.00011\nAge-zero\nprojection:\np = 3.25 × 10−9\nAll\nages\ncombined:\np = 2.67 × 10−7\nAge-zero\nprojection:\np = 2.92 × 10−14\nβ -\nSI\nAll\nages\ncombined:\np = 1.97 × 10−5\nAge-zero\nprojection:\np = 1.14 × 10−18\nAll\nages\ncombined:\np = 5.16 × 10−11\nAge-zero\nprojection:\np = 1.60 × 10−5\nAll\nages\ncombined:\np = 0.00086\nAge-zero\nprojection:\np = 3.01 × 10−9\nAll\nages\ncombined:\np = 0.0027\nAge-zero\nprojection:\np = 1.97 × 10−18\nTable 5: p-values for the Welch comparison tests between Marfan and control patients, for the three\nstiffness measures at different locations\n3.4.3 Linear regressions with age and projection at age-zero comparison308\nFigure 6 and Table 6 present the outcomes of the linear regressions at various aortic locations. Because the quantities309\nwere not normally distributed, the linear regressions were performed after log transformation. Figure 7 and Table 5310\nprovides the results from the Welch comparison test after projecting the data to age-zero. The correlation analyses311\n15\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nFigure 5: Mean and SD of Distensibility, PWV and β-stiffness index for the augmented dataset,\nwithout age consideration.\n16\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nand age-zero projection tests revealed important findings regarding the relationship between PWV, distensibility,312\nβ-stiffness index, age, and Marfan syndrome.313\nNotably, a positive correlation was observed between PWV and age in both Marfan and control patients at all314\naortic locations (p < 0.05). However, the age projection suggested that there was no statistically significant difference315\nin PWV at the root (p = 0.30) and from carotid to femoral ( p = 0.65) between Marfan and control patients at age-316\nzero. Additionally, both MFS and control patients exhibited a negative correlation between distensibility and age317\nat all aortic locations. The age-zero projection demonstrated that distensibility was lower, indicating higher aortic318\nstiffness in MFS patients already at birth. However, the slopes of the linear regressions revealed that distensibility319\ndecreased more rapidly for the control cohort compared to Marfan patients (-0.027 vs. -0.022 for MFS in the root,320\n-0.016 vs. -0.010 in the Arch, and -0.026 vs. -0.021 in the Dao, all values in 10 −3mmHg−1 per year). This result321\ncould also be influenced by the fact that the meta-analysis does not include patients who have had surgery. Since322\npatients who have had surgery tend to be older, this may introduce a bias in the dataset, potentially affecting the323\nobserved rate of distensibility decline in the Marfan cohort. The correlation analyses showed that β-SI was positively324\ncorrelated with age in both Marfan and control patients at all aortic locations ( p < 0.05). After conducting age-zero325\nprojection, the results confirmed that there is a statistically significant difference in β-stiffness index between Marfan326\nand control patients at all locations. Marfan patients had higher values after age-zero projection, indicating stiffer327\ntissues at an early stage of life compared to controls.328\n17\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nROOT AAO ARCH DAO\nPWV (cm/s)\nDistensibility (10\n-3\nmmHg)\nβ-stiffness index\nCAROTID \nFEMORAL\nFigure\n6: Linear regressions of PWV, distensibility and β stiffness index with respect to age at the different locations. Note the log\nscale on the vertical axis, since the regressions were performed on log-transformed values for each quantity to ensure normality.\n18\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nRo\not Aao Arc\nh Dao Carotid-femoral\nPWV\nMarfan:\ny =\n0.015x + 1.92\nR2 = 0.14 ;\np = 1.11 × 10−5\nControl:\ny = 0.015x + 1.84\nR2 = 0.15 ;\np = 6.65 × 10−5\nMarfan:\ny =\n0.007x + 1.51\nR2 = 0.24 ;\np = 1.41 × 10−3\nControl::\ny = 0.0057x + 1.36\nR2 = 0.19 ;\np = 2.77 × 10−2\nMarfan:\ny =\n0.0049x + 1.43\nR2 = 0.13 ;\np = 1.70 × 10−2\nControl:\ny = 0.0082x + 1.21\nR2 = 0.35 ;\np = 2.81 × 10−9\nMarfan:\ny =\n0.011x + 1.41\nR2 = 0.20 ;\np = 2.04 × 10−7\nControl:\ny = 0.013x + 1.11\nR2 = 0.56 ;\np = 3.12 × 10−8\nMarfan:\ny =\n0.0095x + 1.36\nR2 = 0.26 ;\np = 5.17 × 10−8\nControl:\ny = 0.0098x + 1.38\nR2 = 0.18 ;\np = 4.78 × 10−6\nDistensibilit\ny\nMarfan:\ny = −0.022x +\n1.57\nR2 = 0.17 ;\np = 9.25 × 10−7\nControl:\ny = −0.027x + 2.30\nR2 = 0.42 ;\np = 1.26e − 13\nMarfan:\ny = −0.014x +\n1.81\nR2 = 0.24 ;\np = 1.41 × 10−3\nControl:\ny = −0.011x + 2.11\nR2 = 0.19 ;\np = 2.77 × 10−2\nMarfan: y =\n−0.0098x +\n1.98\nR2 = 0.13 ;\np = 1.70 × 10−2\nControl:\ny = −0.016x + 2.42\nR2 = 0.34 ;\np = 2.81 × 10−9\nMarfan: y =\n−0.021x +\n2.023\nR2 = 0.20 ;\np = 2.04 × 10−7\nControl:\ny = −0.026x + 2.62\nR2 = 0.56 ;\np = 3.12 × 10−8\nβ -\nSI\nMarfan:\ny =\n0.022x + 1.54\nR2 = 0.19 ;\np = 1.81 × 10−7\nControl:\ny = 0.026x + 0.81\nR2 = 0.44 ;\np = 3.58 × 10−14\nMarfan:\ny =\n0.011x + 1.37\nR2 = 0.15 ;\np = 1.35 × 10−2\nControl:\ny = 0.011x + 0.93\nR2 = 0.19 ;\np = 2.77 × 10−2\nMarfan:\ny =\n0.0098x + 1.18\nR2 = 0.13 ;\np = 1.70 × 10−2\nControl:\ny = 0.016x + 0.74\nR2 = 0.34 ;\np = 2.81 × 10−9\nMarfan:\ny =\n0.020x + 1.14\nR2 = 0.24 ;\np = 5.64 × 10−4\nControl:\ny = 0.037x − 0.027\nR2 = 0.89 ;\np = 3.10 × 10−10\nTable 6: Results of the linear regression equations\n4 Discussion329\n4.1 Key findings in the literature330\nThe diameter of blood vessels is a commonly used indicator for detecting biomechanical changes, and abnormal331\ndiameters at specific locations in the aorta are considered signs of disease. Diameter was reported to be larger in332\nMarfan patients at the root and Aao. These results align with previously observed patterns in pediatric Marfan333\npatients, where dilatation typically begins at the sinus of Valsalva, followed by the sino-tubular junction (STJ), and334\nis less frequent in the descending aorta [48]. The reported higher diameters at the root in MFS patients also provide335\nsupport for the current guideline of measuring the aortic root to plan prophylactic surgery.336\nAcross most aortic regions, studies reported a significantly higher PWV in MFS when compared to control cohorts,337\nbut only in the already dilated aortas. Indeed, PWV was not as sensitive to changes in aortic biomechanics in the338\ninitial phases of aortic dilatation, e.g., compared to distensibility. This observation underscores the importance of339\nconsidering the stage of aortic dilatation when interpreting PWV values and highlights the complexity of using PWV340\nas a sole predictor for aortic dilatation in MFS patients. While it may provide valuable information about aortic341\nstiffness, its ability to precisely predict aortic growth is limited. Combining PWV with other relevant parameters,342\nsuch as distensibility, may yield more comprehensive insights into the dynamics of aortic changes in MFS and aid in343\nmaking accurate clinical assessments.344\nThe results derived from the studies included in this review provided evidence that change in distensibility values345\ncan serve as an effective mean to detect alterations in the biomechanical properties of the aorta. Specifically, a346\ndecrease in distensibility was indicative of increased tissue stiffness within the aortic wall. Distensibility was lower at347\nall aortic locations even in juvenile non-dilated aortas, with values half of those in the healthy patients. A significant348\ncorrelation between distensibility and age was also put forward. Finally, longitudinal studies showed that a higher349\ndistensibility is associated with higher chances of developing an aneurysm in the Aao and Dao. Although sensitive to350\nlocation, these findings underscore the potential utility of distensibility as an early indicator of aortic biomechanical351\nchanges in Marfan patients.352\n19\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nFigure 7: Mean and SD in log-scale of distensibility, PWV and β-stiffness index projected at zero age.\nThe statistical tests were run on log-transformed values for each quantity.\n20\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nThe results across the studies indicated that β-SI values were notably higher in the root, Aao, and Dao among353\npatients with Marfan Syndrome in comparison to control subjects, even in non-dilated aortas. It was positively354\ncorrelated with the rate of aortic dilatation, emphasizing its role as a valuable indicator. Unlike baseline aortic355\ndimensions, β-SI appeared to be a better predictor of the progression of aortic dilatation. However, it is worth noting356\nthat, after 40 years of age, the control and MFS cohorts could not be distinguished using the β-SI. Interestingly,357\nyounger MFS patients had higher β-SI values compared to their age-matched controls, but this distinction diminished358\nin older populations. This particular observation offers insights on progression of aortic stiffness in MFS patients as359\nthey age. It may suggest that altered aortic stiffness eventually leads to convergence between the Marfan and control360\ncohorts after a certain age threshold.361\n4.2 Meta-analysis results362\nIn the meta-analysis, in consensus with the literature, diameter was found to be significantly higher in MFS at the363\nroot, which align with the current guideline of measuring the aortic root to plan prophylactic surgery. Interestingly,364\nno difference was found in the Aao and Dao. In this case, however, no age consideration was possible to due lack365\nof data reporting diameter with respect to age. Combining all patients regardless of their age includes bias when366\ncomparing Marfan and control since diameter depends highly on age, weight and height of the patient. Diameter367\nassessment adjusted for body surface area, which has been found to be more useful than age, height, or weight alone368\nfor the measuring the size of the aorta [49], would have possibly led to different statistical results.369\nThe meta-analysis results also provide valuable insights into the relationship between aortic stiffness measures,370\nage, and Marfan syndrome. Firstly, it was observed that without considering age, Marfan patients exhibited higher371\nPWV values at all locations, except for the root and the carotid-femoral region. It is particularly interesting to note372\nthat distinctions between cohorts were challenging when assessing PWV at the carotid-femoral region, which is the373\nmost commonly used PWV measurement in clinical practice. This observation can be explained by the fact that374\ncarotid-femoral PWV covers a substantial portion of the aortic tract and may not be sensitive to local variations in375\ntissue stiffness. On the other hand, PWV was found to be approximately two times higher at the root. However, the376\nroot’s relatively small length may lead to difficulties in tracking the foot of the pulse wave, resulting in the considerably377\nlarge standard deviation observed in patients. PWV at the root is rarely utilized in clinical practice and failed to378\ndistinguish between the two cohorts effectively. Furthermore, a positive correlation was identified between PWV and379\nage in both Marfan and control patients across all aortic locations. However, the age-zero projection suggested that380\na statistically significant difference in PWV exists at all locations, except at the root and the carotid-femoral region.381\nThis notable result implies that age plays a significant role in the evolution of PWV. More importantly, it indicates382\nthat the difference between Marfan and control patients does not develop with age. Instead, Marfan patients are383\nborn with higher PWV, indicating stiffer aortic tissues. It is worth highlighting that PWV measurements taken at384\nthe carotid-femoral region and the root fail to capture these inherent differences.385\nBoth Marfan and control patients were found to exhibit a negative correlation between distensibility and age386\nat all aortic locations. The age-zero projection further emphasized that distensibility is lower, signifying increased387\naortic stiffness in MFS patients, even at a young age. Notably, the slopes of the linear regressions indicated that388\ndistensibility decreases at a faster rate for the control cohort compared to Marfan patients. It is essential to note389\nthat this observation might be influenced by the absence of patients past 40 years old in the dataset, introducing a390\npotential bias.391\nAdditionally, our analysis demonstrated that β-stiffness index was positively correlated with age in both Marfan392\nand control patients at all aortic locations. Before and after conducting age-zero projection, the results affirmed a393\nstatistically significant difference in β-stiffness index between Marfan and control patients at all locations. These394\nfindings suggest that Marfan patients exhibit higher β-SI values even at an early stage of life, indicating stiffer aortic395\ntissues compared to controls.396\nThe results at age-zero projection provide a more reliable assessment of aortic stiffness in Marfan patients and397\nunderscore the importance of considering age as a confounding factor in such studies. Overall, the data indicates398\nthat distensibility and β-index are consistently altered in Marfan patients compared to controls, while PWV still399\nshows location-specific differences between the two groups before and after age-zero projection.400\n21\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\n4.3 Recommendations for future studies401\nHandling missing data poses a significant challenge in systematic quantitative reviews. This review underscores402\nthe importance of reporting data to facilitate statistically robust and comprehensive meta-analyses. Rather than403\nreporting meand and SD, we recommend that studies report individual data points. This could be achieved through404\nsupplementary dataset if needed. The incorporation of a substantial number of participants and the diverse range of405\nstudy designs greatly contributes to the robustness and depth of the findings presented in this review. However, if406\neach patient had reported diameter, age and stiffness measure, it would have allowed for a more thorough statistical407\nanalysis (such as multivariate regression).408\nIt is noticeable that there is a lack of studies focusing on specific age ranges and cohorts with more than 40409\npatients. For pediatrics, only one multicenter study comprises 608 patients [35]. A plausible explantation could be410\nthat MFS is rarely diagnosed in paediatric populations since patients do not appear phenotypically different. Not411\nall paediatric patients have family history eihter, which makes the diagnosis at an early stage of life challenging.412\nSimilarly, no studies focused on patients past 40 years old, which represents a turning point in stiffness increase413\naccording to Wit et al. [27]. This absence could potentially be attributed to the fact that aortic surgeries are414\ntypically performed before patients reach this age, resulting in limited accessible data for older patients.415\n4.4 Limitations416\nRegarding limitations, we acknowledge that all pertinent studies may not have been captured in our search. Our417\nsearch criteria might have missed studies that were not explicitly categorized under, or did not explicitly reference a418\nMarfan syndrome diagnosis. Since Marfan syndrome can be misdiagnosed for other connective tissue disorders caused419\nby pathogenic variants in genes other than FBN1, studies published before the revised Ghent criteria were excluded.420\nHowever, they likely include true Marfan patients and provide valuable insights. Similarly, mild Marfan syndrome421\ncases and cases of suspected but not yet verified Marfan syndrome, were possibly overlooked in this present work.422\nDespite the revised Ghent criteria, Marfan syndrome clinically overlaps with other connective tissue disorders, such as423\nLoeys-Dietz syndrome, and distinguishing them is challenging in the absence of a molecular diagnosis. Consequently,424\nindividuals with mutations in proteins related to the TGF- β pathway might receive a Marfan syndrome diagnosis425\nagainst the Ghent nosology and be included in this study.426\nWhile this work does touch upon aortic diameter, it is important to note that a significant portion of the existing427\nliterature primarily focuses on aortic diameter in Marfan patients, but these studies were not encompassed in this428\nreview. Instead, discussions concerning diameter in this review are derived exclusively from data within the selected429\npapers that primarily address aortic stiffness measures.430\nThe aortic sites and regions were not defined identically between the selected papers. To facilitate the reporting431\nof results and minimize potential inconsistencies, we made efforts to categorize them into five main regions: Root,432\nAao, Arch, Dao and Carotid-femoral, although minor variations may remain. The data gap in specific age brackets433\nis an essential consideration when interpreting the findings of this review. The review’s strength lies in its ability to434\ncompile and analyze aortic stiffness in different populations. However, the absence of age-specific studies, especially435\nin the pediatric and older age groups, highlights a potential area for future research.436\nConcerning the meta-analysis, despite our efforts to address missing data, several factors introduced bias into the437\nstatistical tests. This bias stems from theoretical conversion equations, which cannot precisely mimic physiological438\nbehaviour, as well as the absence of individual data points and the lack of age-associated values for each data point.439\nSimilarly, conducting an age projection involves making inferences beyond the data range, which may not align440\nwith in-vivo behaviour. The regression analysis with age was conducted solely on data that included individual data441\npoints with corresponding age. Additionally, the predictive power of aortic stiffness measures could not be thoroughly442\ninvestigated in the meta-analysis due to the absence of articles reporting individual values for patients followed at443\nvarious ages. Lastly, examining diameter as a potential confounding variable was unfeasible because of the scarcity444\nof studies reporting individual data points for stiffness measures, alongside corresponding age and diameter values.445\n4.5 Conclusion446\nTo the best of the authors’ knowledge, this is the first systematic review and meta analysis investigating how in-447\nvivo aortic stiffness measures can be early markers of aortic disease in Marfan syndrome, and their prediction of448\naortic dilatation. Our study emphasizes the importance of using a combination of parameters, including diameter449\n22\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint \n\nmeasurements and stiffness indices, to obtain a more comprehensive evaluation of aortic disease in MFS patients.450\nThis approach can provide a deeper understanding of disease progression and assist clinical decision making.451\nFunding452\nThis study was partially funded by the Engineering and Physical Sciences Research Council (EP/N02124X/1) and453\nUniversity of Glasgow’s College of Science and Engineering via PhD studentship.454\nData availability statement455\nAll data produced in the present study are available upon reasonable request to the authors456\n23\n . 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CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted January 7, 2024. ; https://doi.org/10.1101/2024.01.05.24300824doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}