Circulating Transforming Growth Factor-β in Marfan Syndrome
Background— Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-β (TGF-β). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-β activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-β might be mirrored in circulating TGF-β concentrations.
Methods and Results— Serum obtained from MFS mutant mice (Fbn1C1039G/+) treated with losartan was analyzed for circulating TGF-β1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-β1 concentrations increased with age and were elevated in older untreated Fbn1C1039G/+ mice compared with wild-type mice (P=0.01; n=16; mean±SEM, 115±8 ng/mL versus n=17; mean±SEM, 92±4 ng/mL). Losartan-treated Fbn1C1039G/+ mice had lower total TGF-β1 concentrations compared with age-matched Fbn1C1039G/+ mice treated with placebo (P=0.01; n=18; 90±5 ng/mL), and circulating total TGF-β1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-β1 levels and aortic root diameters in Fbn1C1039G/+ and wild-type mice (P=0.002). In humans, circulating total TGF-β1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15±1.7 ng/mL versus n=74; 2.5±0.4 ng/mL). MFS patients treated with losartan (n=55) or β-blocker (n=80) showed significantly lower total TGF-β1 concentrations compared with untreated MFS patients (P≤0.05).
Conclusions— Circulating TGF-β1 concentrations are elevated in MFS and decrease after administration of losartan, β-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.
Received December 7, 2008; accepted June 1, 2009.
Marfan syndrome (MFS) is a systemic connective tissue disorder that affects ≈1 in 5000 individuals.1,2 It is inherited as an autosomal dominant trait and is caused by mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1).3 FBN1 mutations lead to defects in multiple organ systems. Aortic root dilatation is the leading cause of morbidity and mortality in MFS.1,4 Several studies, based mainly on the analysis and creation of genetically engineered mouse models, have challenged the definition of MFS as a simple structural disorder of the connective tissue.5–8 It has been shown that many clinical manifestations associated with MFS, including aortic root dilatation, pulmonary emphysema, atrioventricular valve changes, and skeletal muscle myopathy, are induced by altered transforming growth factor-β (TGF-β) activation and signaling.5–7,9 A mouse model heterozygous for a mutant Fbn1 allele encoding a cysteine substitution in an epidermal growth factor-like domain of fibrillin-1, Fbn1C1039G/+, was shown to develop pathological changes in the aorta and aortic root enlargement that closely mimic those seen in humans with MFS accompanied by excessive TGF-β signaling in the aortic root wall.7 Most importantly, TGF-β antagonism through systemic administration of TGF-β neutralizing antibody prevented the development of pathological changes in the aortic wall and progressive aortic dilatation.7 TGF-β antagonism also rescued other manifestations of MFS, including muscle regeneration, architecture, and strength, pulmonary alveolar septation, and mitral valve morphology in the mouse model.5,8 Administration of losartan, an angiotensin II type 1 receptor blocker (ARB) known to antagonize TGF-β signaling through inhibition of TGF-β expression and activation,10 normalized aortic root growth and dimensions in the Fbn1C1039G/+ mice and resulted in an aortic wall architecture that was indistinguishable from that of wild-type mice.7 The therapeutic benefit of losartan was recently replicated in a small pediatric cohort with a severe form of MFS.11 Losartan, either alone or in addition to β-blocker therapy, led to a reduction in the rate of change in the aortic root diameter compared with β-blocker therapy alone.11 Taken together, these data suggest that dysregulation of TGF-β, which is an autocrine and paracrine growth factor with involvement in a wide range of biological processes, contributes to the multisystem pathogenesis of MFS.4,7,11
Editorial see p 464
Clinical Perspective on p 532
TGF-β is secreted from the cell in the context of a large latent complex (LLC) that includes the active cytokine, its processed N-terminal propeptide (termed latency-associated peptide), and 1 of 3 latent TGF-β binding proteins (LTBP1, LTBP3, or LTBP4). The LLC is targeted to the matrix by virtue of interactions between LTBPs and both fibronectin and fibrillins. Current models suggest that fibrillin-1 deficiency leads to failed matrix sequestration of the LLC of TGF-β, with consequent excessive TGF-β activation and signaling. In this light, pathogenic events might correlate with circulating TGF-β concentrations. If so, then systemic administration of losartan in the mouse models of MFS should decrease circulating TGF-β concentrations. If transferable to humans, circulating TGF-β might serve as a promising marker for prognostication and for individualizing therapeutic regimens in MFS.
All mouse and human protocols were approved by the institutional review board of Johns Hopkins University School of Medicine and MedStar Research Institute, Baltimore, Md.
The mouse line heterozygous for Fbn1 mutation C1039G (Fbn1C1039G/+) has been described previously.5,6 All analyses were performed after back-crossing this mutation into the C57BL/6J background (>9 generations), allowing valid comparisons between litters. Fbn1C1039G/+ mice were treated with oral losartan (0.6 g/L in drinking water; n=18) or placebo (n=37) beginning at 7 weeks of age and continuing until they were euthanized; wild-type littermates received only placebo (n=41). A small subgroup of Fbn1C1039G/+ mice was treated with a higher dose of oral losartan (1.2 g/L in drinking water; n=3). All mice were euthanized with an inhalation overdose of halothane (Sigma-Aldrich, St Louis, Mo). Blood samples from mice were collected from the right ventricle immediately after they were euthanized and were allowed to clot for 2 hours at room temperature before being centrifuged for 20 minutes at 2000g. Serum was removed, aliquoted, and stored immediately at −80°C until further analysis.
Plasma samples and clinical data from 207 patients diagnosed with MFS were collected through the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Plasma samples from 74 healthy individuals obtained at the National Institute on Aging served as controls. Selection criteria for control patients were as follows: no cardiovascular disease or drugs, no cancer, no inflammatory of autoimmune disorders, no diabetes, and no drugs that could affect the extracellular matrix. Blood samples in MFS and control patients were collected on ice with EDTA used as an anticoagulant. Samples were centrifuged at 3000g for 15 minutes at 4°C, and plasma samples were stored immediately at −80°C until further analysis.
Enzyme-Linked Immunosorbent Assay for TGF-β
TGF-β1 concentrations in mice samples were measured by enzyme-linked immunosorbent assay with the Quantikine TGF-β1 immunoassay (R&D Systems, Minneapolis, Minn; catalog No. MB100M). The minimum detectable concentration of TGF-β1 in this assay ranges from 1.7 to 15.4 pg/mL, and there is <1% cross-reactivity with the latent TGF-β1 complex. Total TGF-β1 concentrations were measured by first acid-activating (with 1N HCl) latent TGF-β1 to immunoreactive TGF-β1; free (active) TGF-β1 levels were measured without first acid-activating the sample. The enzyme-linked immunosorbent assay was performed according to the manufacturer’s protocol. Briefly, the wells are precoated with monoclonal antibody specific for TGF-β1. Standards, controls, and samples were added and incubated for 2 hours. After a washing, an enzyme-linked polyclonal antibody specific for TGF-β1 was added. After another washing, samples were incubated with a substrate solution for 30 minutes, and the color reaction was stopped by addition of a diluted HCl solution. The optical density of each well was measured immediately with a microplate reader at 450 nm, and the wavelength correction was set to 570 nm. All samples were run in duplicate.
Human EDTA plasma samples were assayed for levels of total TGF-β1 with the use of a commercially available, ruthenium-based electrochemiluminescence platform (Meso Scale Discovery, Gaithersburg, Md) following the manufacturer’s recommendations. To be able to measure total TGF-β1, samples were first acid-activated (with 1N HCl) before assaying. All samples were run in duplicate. The lowest level of detection for total TGF-β1 was 4±2.6 pg/mL.
We considered TGF-β1 results (in mice and in human samples) valid when recovery (expected concentration divided by calculated concentration multiplied by 100) of the standards/calibrators was 100±20%, the coefficient of variation was <20%, intra-assay coefficient of variation was <10%, and the interassay coefficient of variation was <20%. A run was considered valid when >85% of the samples were within these specifications.
Aortic Root Diameters: Echocardiography
Transthoracic echocardiograms (n=39) were performed on awake, nonsedated mice with the use of the VisualSonics Vevo 660 V1.3.6 imaging system and a 40- or 60-MHz transducer (model RMV603, VisualSonics, Inc, Toronto, Ontario, Canada). The aorta was imaged in the parasternal long-axis view, and 3 measurements were obtained at the level of the sinuses of Valsalva (SOV) by an observer blinded to genotype and treatment arm. All echocardiographic studies were performed by 2 individuals with extensive experience with mouse echocardiography.
In patients with MFS, aortic root dimensions (SOV) were obtained through transthoracic echocardiography by multiple echocardiographers. All echocardiographic data were collected in the GenTAC registry before measurements of circulating TGF-β1 concentrations were performed. Measurements of the maximal aortic root diameter were taken by the leading-edge technique, consistent with the current American Society of Echocardiography guidelines.12 A Z score, which represents the standard deviation from the mean aortic diameter normalized for the patient’s body surface area and age, was calculated from each echocardiographic measurement with the use of standard algorithms.
Continuous variables were presented as mean±SEM. Comparisons of circulating TGF-β1 concentrations among the groups were conducted by 1-way ANOVA. If significance was found for group effect, pairwise comparisons between the groups were made with the unpaired t test. Associations between circulating TGF-β1 concentrations and SOV diameters were studied with the use of the Pearson correlation and linear regression analysis and illustrated in scatterplots with confidence bands on a regression line. For comparisons of nonparametric data, the χ2 test was used. Two-sided P values of <0.05 were considered to indicate statistical significance for all statistical tests and models. SPSS statistical software 9.0 was used for all analyses.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
One-way ANOVA showed high group effects for circulating total and free TGF-β1 concentrations (P=0.002, P<0.0001). Circulating total TGF-β1 concentrations increased with age in Fbn1C1039G/+ and wild-type mice (Figure 1A and 1B). Total TGF-β1 was higher in samples obtained from 6- to 10-month-old Fbn1C1039G/+ mice compared with age-matched wild-type mice (P=0.01; n=16; mean±SEM, 115±8 ng/mL versus n=17; mean±SEM, 92±4 ng/mL; Figure 1A). Losartan-treated Fbn1C1039G/+ mice had lower total TGF-β1 concentrations compared with age-matched Fbn1C1039G/+ mice treated with placebo (P=0.01; n=18; 90±5 ng/mL versus n=16; 115±8 ng/mL; Figure 1A). Circulating total TGF-β1 in losartan-treated Fbn1C1039G/+ mice and age-matched wild-type mice were indistinguishable (P=0.8; Figure 1A). A subgroup of Fbn1C1039G/+ mice (n=3) treated with a higher dose of losartan (1.2 g/L in drinking water) showed a further reduction of circulating TGF-β1 concentrations (Figure 1A). Changes in circulating free TGF-β1 levels mirrored the changes seen in total TGF-β1 (Figure 1B). Correlation was observed between circulating total TGF-β1 and free TGF-β1 concentrations in matched samples (n=43; r=0.6, P<0.0001).
Aortic root diameters (SOV) were smaller in 6- to 10-month-old wild-type mice compared with age-matched untreated Fbn1C1039G/+ mice (P<0.0001; n=15; mean±SEM, 1.69±0.02 mm versus n=10; mean±SEM, 2.23±0.11 mm). Losartan treatment in Fbn1C1039G/+ mice led to smaller SOV dimensions compared with age-matched untreated Fbn1C1039G/+ mice (P<0.0001), and losartan-treated Fbn1C1039G/+ mice and age-matched wild-type mice showed indistinguishable SOV dimensions, as shown previously.7 SOV diameters in untreated Fbn1C1039G/+ and wild-type mice correlated with circulating total TGF-β1 (r=0.6, P=0.002) and circulating free TGF-β1 concentrations (r=0.6, P<0.001; Figure 1C and 1D).
Baseline demographics for patients diagnosed with MFS (n=207) and control individuals (n=74) are provided in the Table. MFS patients were younger, and there were more male subjects within the MFS group compared with the controls. Previous aortic root surgery and cardiovascular drug therapy, including losartan, other ARBs, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors, occurred only in people with MFS.
One-way ANOVA showed high group effects for circulating total TGF-β1 concentrations (P<0.0001). Circulating total TGF-β1 concentrations were elevated in MFS patients without cardiovascular drug therapy compared with the control individuals (P<0.0001; n=53; mean±SEM, 15±1.7 ng/mL versus n=74; mean±SEM, 2.5±0.4 ng/mL; Figure 2A). MFS patients treated with losartan (n=55; of those, 45 patients received a combination of losartan and β-blocker therapy) showed significantly lower total TGF-β1 concentrations compared with untreated MFS patients (P=0.05; 11±1.4 ng/mL versus 15±1.7 ng/mL; Figure 2A). Similarly, total TGF-β1 concentrations were lower in MFS patients treated only with β-blockers (P=0.03; n=80; 11±1.2 ng/mL versus 15±1.7 ng/mL; Figure 2A). A subgroup of MFS patients treated with ACE inhibitors (n=12; of those, 10 patients received a combination of ACE inhibitor and β-blocker therapy) showed a tendency toward lower total TGF-β1 concentrations (P=0.1; 12.7±2.8 ng/mL versus 15±1.7 ng/mL; Figure 2A). MFS patients with losartan, β-blocker, or ACE inhibitor therapy showed significantly higher circulating TGF-β1 levels compared with the control individuals (P<0.0001). Correlations between circulating total TGF-β1 concentrations and SOV diameters or Z scores, respectively, in MFS patients were not significant (Figure 2B). Circulating total TGF-β1 concentrations were neither sex nor age dependent in people with MFS and healthy control individuals (Figure 2C and 2D).
Recent studies have established the critical contribution of dysregulated TGF-β signaling to the progression of disease in MFS.5–8 Mouse models have validated TGF-β antagonism as a productive treatment strategy for both the cardiovascular and systemic manifestations of MFS, including the use of losartan, and early experience suggests that this protection may extend to people with MFS.7,11 Despite significant progress regarding the pathogenesis and treatment of MFS, many obstacles remain. In a small observational study of children with severe MFS treated with losartan, all showed at least some reduction in aortic root growth compared with their progression on prior medical therapy, but the degree of response was variable.11 Although widespread adoption of the practice of performing aortic root surgery once the dimension exceeds 5.0 cm in adults has greatly reduced mortality due to aortic dissection, meaningful guidelines for children are lacking, and death due to root dissection continues to be observed in both age groups. Even among patients with successful prophylactic aortic root replacement, there is risk of dissection of other aortic segments, prominently of the proximal descending thoracic aorta, and this occurs in many patients without prior dilatation.
In the absence of empirical data, the dose of losartan or other medications currently used in patients with MFS is based largely on dosing regimens for hypertension. Although the weight-based dosing for losartan used in mice was considerably higher than that for people, metabolic differences between species preclude extrapolation.7 Consideration of dosing may be particularly important because ultrahigh doses of ARBs and other medications have been suggested to have enhanced efficacy in treating other TGF-β–related diseases in both mice and people.7,8,11 Furthermore, natural genetic variation in people, including genes encoding regulators of drug metabolism or the renin-angiotensin system, can influence both the effective level of and intrinsic response to ARBs, ACE inhibitors, and β-blockers. A similar “one size fits all” philosophy for surgical management is intuitively limited. Taken together, these observations highlight the need for an informative prognostic and therapeutic marker in MFS. The lack of robust phenotype-genotype correlations in MFS suggests that FBN1 genotype fails to accommodate this need.
Despite gaps in our understanding of the precise mechanism by which fibrillin-1 deficiency correlates with increased TGF-β signaling, current data are consistent with a model in which LLC that fails to be sequestered by the extracellular matrix is more bioavailable for or prone to activation in a protease-dependent (eg, matrix metalloproteinases or plasmin) or -independent (eg, through the action of thrombospondin-1 or selected integrins) manner.13–16 Curiously, the levels of selected TGF-β activators (including matrix metalloproteinase-2, matrix metalloproteinase-9, and thrombospondin-1) and ligands have been shown to be elevated in the tissues of patients with MFS, including the aortic wall.17 It remains to be determined whether this is the result of positive autoregulation by TGF-β or either proximal or parallel events. Nevertheless, blockade of the angiotensin II type 1 receptor with ARBs has been shown to diminish the expression of TGF-β, its receptor, and potential activators, including thrombospondin-1 and matrix metalloproteinases, providing multiple potential mechanisms of protection from TGF-β–induced pathogenic events.7 In agreement with this paradigm, we now report that a genetically defined mouse model of MFS that faithfully recapitulates most aspects of the disease, including progressive aortic root dilatation, shows elevated circulating levels of both latent and active TGF-β. Furthermore, circulating TGF-β levels show close correlation with aortic root dimension in mice that have or have not been treated with losartan, diminish on treatment in a dose-dependent manner, and are fully normalized in mice that show a robust therapeutic response.
Although the use of circulating TGF-β levels to individualize patient counseling and management is appealing because the assay is monitoring a central and direct effector of disease progression, it is essential to gain a better understanding of how and why events in tissues and markers in the circulation correlate. The simplest hypothesis posits that complexed TGF-β and free TGF-β simply leach into the circulation because of failed matrix sequestration and increased activation of the LLC, respectively. It is also formally possible that increased circulating active TGF-β contributes to altered cellular and tissue performance. This seems unlikely, however, given the relatively high pericellular and matrix concentrations of TGF-β that result from direct secretion compared with that in the circulation. The description of a patient with hemi-MFS, as a result of discrete lateral somatic mosaicism, also argues against a major contribution of circulating TGF-β to the disease phenotype.18
In agreement with our results, the ability of ARBs to lower circulating TGF-β levels has been observed in other disease processes, and perindopril was shown to lower elevated circulating TGF-β levels in a small group of patients with MFS.19 Although we observed a significant increase in the amount of total TGF-β in MFS patients versus controls, the levels of free TGF-β were extremely low in both groups, precluding a meaningful comparison. This is not surprising because human latent TGF-β1 has a half-life of ≈90 minutes, whereas free TGF-β1 has a half-life of only 2 minutes.14,15 It is possible that modified handling or processing of human samples would allow for valid measurements.
It is intriguing that MFS patients treated with β-adrenergic receptor blocking agents (β-blockers) showed a significant decrease in circulating levels of TGF-β. Although prior studies have linked β-adrenergic and TGF-β signaling, the mechanistic details are not well established. Patients with dilated cardiomyopathy–associated fibrosis showed decreased expression of TGF-β1 and its target genes encoding types I and III collagens on treatment with β-blockers.20 Treatment of Marfan mouse models with atenolol reduced TGF-β expression and signaling, although this effect appeared restricted to early age groups.21 In agreement with this finding, Marfan mice treated with propranolol showed a significant reduction in aortic root size compared with placebo-treated animals. However, there was no apparent effect on TGF-β signaling in the aortic wall in older animals, and the extent of long-term protection was far less than that achieved with losartan.7 The finding that TGF-β can positively stimulate its own expression and activation and can increase β-adrenergic receptor density and signaling in the cardiovascular system22 highlights the potential for both auto- and cross-induction of these signaling cascades. The extent to which circulating TGF-β levels serve as a valid surrogate for critical pathogenic events in the tissues of MFS patients may prove both dynamic and context dependent. The emerging view is that β-blockers can reduce TGF-β expression, whereas ARBs reduce both expression and activation. In this light, the reduction in circulating TGF-β seen while a patient is on β-blockers or ARBs may herald protection in tissues or stages in disease progression in which TGF-β signaling is limited by TGF-β expression levels. In other contexts in which excessive TGF-β activation is sufficient to achieve pathogenic signaling thresholds, the prognostic value of a drop in circulating TGF-β levels may be unique to patients receiving ARBs. This important issue clearly warrants further study.
We did not observe close correlation between circulating TGF-β and aortic root size or Z score in people with MFS. There are many possible explanations. First, surrogate markers in human samples often show a much higher variability than seen in mice with the same genetic background and standardized environment. Second, our study mainly focused on adults and was enriched for people with milder disease and who were receiving medical therapy that could modify pathogenic events, including TGF-β levels. Finally, the aortic root is likely a minor contributor to circulating TGF-β levels compared with other tissues that are affected in MFS, including skeletal muscle, skin, and lung. Although there is high concordance between the severity of aortic and systemic disease in the various inbred mouse strains with Fbn1 mutations and in people at the extremes of disease severity, this is not the case in people with more moderate presentations of MFS. In this light, the high correlation between circulating TGF-β levels and aortic performance in mice might be recapitulated in defined subsets of patients. Even if there is little intrinsic prognostic value to a snapshot measurement of circulating TGF-β in people with MFS, there remains a high probability of obtaining important information for individual trends observed during the progression of disease and in response to therapy.
GenTAC participating centers are as follows: Johns Hopkins University, Kathryn W. Holmes, MD, Harry C. Dietz, MD, Williams Ravekes, MD, Kira Lurman, RN; University of Texas–Houston, Dianna M. Milewicz, MD, PhD, Claire Noll, MS, CGC; Baylor College of Medicine, Scott A. LeMaire, MD, Irina Volguina, PhD; Oregon Health and Science University, Cheryl L Maslen, PhD, Howard K. Song, MD, PhD, Victor Menashe, MD, Jessica D. Kushner, MS, CGC; University of Pennsylvania, Reed E. Pyeritz, MD, PhD, Joseph E. Bavaria, MD, Megan Morales; Weill Medical College of Cornell University, Craig T. Basson, MD, PhD, Richard Devereux, MD, Jonathan W. Weinsaft, MD, Deborah McDermott, MS, CGC; University of Michigan, Kim Eagle, MD; National Heart, Lung, and Blood Institute, H. Eser Tolunay, PhD, Patrice Desvigne-Nickens, MD, Mario P. Stylianou, PhD, Megan Mitchell, MPH; RTI International, Barbara L. Kroner, PhD, Donald Brambilla, PhD, Tabitha Hendershot, Danny Ringer, Meg Cunningham, Mark Kindem.
We thank the GenTAC investigators, collaborators, and coordinators. Dr Matt thanks the Swiss National Foundation, the Novartis Foundation, and the Hippocrate Foundation Basel for financial support. Dr Schoenhoff thanks the Swiss National Foundation, the Novartis Foundation, and the intramural research grant program from the Department of Cardiovascular Surgery, University of Berne for financial support. Drs Loeys and De Backer are Senior Clinical Investigators of the Fund for Scientific Research Flanders. Dr McDonnell thanks Leslie Sloper, National Institute on Aging–Advanced Studies in Translational Research on Aging unit staff, and National Institute on Aging core laboratory for facilitation of sample collection and processing. We thank Hendrik Tevaearai, MD, and Thierry Carrel, MD, Inselspital Berne, Switzerland, for critical reading and editing of the manuscript. We thank Brigitta Gahl, Inselspital Berne, for support in statistical analyses.
Sources of Funding
Dr Matt is supported by the Swiss National Foundation, the Novartis Foundation, and the Hippocrate Foundation Basel. Dr Van Eyk is supported by grants from the National Heart, Lung, and Blood Institute Proteomic Initiative (contract NO-HV-28120), the Daniel P. Amos Family Foundation, and the Institute for Clinical and Translational Science Award (grant NO 1U54RR023561-01A1). Dr Dietz is supported by the National Institutes of Health, the Howard Hughes Medical Institute, the William S. Smilow Center for Marfan Syndrome Research, and the National Marfan Foundation. Dr McDonnell, Ben Griswold, and Dr Carlson are supported by intramural funds originating at the National Institute on Aging/National Institutes of Health. Dr Schoenhoff is supported by the Swiss National Foundation and the Novartis Foundation.
None other than those noted in the aforementioned Sources of Funding.
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Recent evidence suggests that transforming growth factor-β (TGF-β) antagonism through losartan may be an effective treatment for Marfan syndrome (MFS). In the absence of empirical data, the dose of losartan or other medications currently used in people with MFS is based largely on dosing regimens for hypertension. Consideration of dosing may be particularly important because natural genetic variation in MFS can influence effective levels of and intrinsic response to drug therapy. This highlights the need for an informative biomarker—prognostic, therapeutic, or both—in MFS. We report that a genetically defined mouse model of MFS, which recapitulates many manifestations of the disease including progressive aortic root dilatation, shows elevated circulating TGF-β concentrations. Furthermore, circulating TGF-β levels show close correlation with aortic root dimension in mice, diminish on treatment with losartan in a dose-dependent manner, and are fully normalized in mice that show a robust therapeutic response. As in the mouse model, we observed elevated circulating TGF-β concentrations in people diagnosed with MFS, and those levels decreased after treatment with losartan or β-blocker. However, we did not observe a close correlation between circulating TGF-β levels and the aortic root size or Z scores in humans. The use of circulating TGF-β to individualize patient counseling and management is appealing because the assay is monitoring a central and direct effector of disease progression. Even if there is little intrinsic prognostic value to a snapshot measurement of circulating TGF-β, observing TGF-β over time in the individual patient might yield important information on progression of the disease, response to therapy, or both.
Participating centers for the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) are shown in the Appendix.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.841981/DC1.