Author + information
- Received November 2, 2016
- Revision received March 30, 2017
- Accepted April 4, 2017
- Published online June 5, 2017.
- Judith Z. Goldfinger, MDa,∗ (, )
- Liliana R. Preiss, MSb,
- Richard B. Devereux, MDc,
- Mary J. Roman, MDc,
- Tabitha P. Hendershot, BAb,
- Barbara L. Kroner, PhDb,
- Kim A. Eagle, MDd,
- GenTAC Registry Consortium
- aZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bBiostatistics and Epidemiology Division, Research Triangle Institute International, Rockville, Maryland
- cDivision of Cardiology, Weill Cornell Medical College, New York, New York
- dDepartment of Cardiology, University of Michigan Health System, Ann Arbor, Michigan
- ↵∗Address for correspondence:
Dr. Judith Z. Goldfinger, Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1030, New York, New York 10029.
Background Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL.
Objectives This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data.
Methods QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity.
Results In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL.
Conclusions In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity.
Marfan syndrome (MFS) is a hereditary, autosomal dominant disorder due to mutations in the fibrillin-1 gene, that affects connective tissue in multiple organs, most notably the eyes, skeleton, and aorta, with increased risk for thoracic aortic aneurysm and dissection. With advances in aortic surgery over the past 40 years, survival for people with MFS has increased from the third or fourth decade to the eighth (1). However, there continues to be substantial morbidity associated with MFS, including the sequelae of multiple surgeries and lifelong medical therapy (2–4). Not surprisingly, a growing body of literature suggests impaired quality of life (QOL) in patients with MFS (5–11), with most studies using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to assess QOL (5–13). Prior studies, however, were limited by small sample sizes and were therefore not able to identify independent factors associated with better or worse QOL.
The SF-36 is a widely used and extensively validated questionnaire that assesses health-related QOL. The questionnaire is subdivided into the Physical Component Score (PCS) and Mental Component Score. Because previous studies found that MFS predominantly affected the PCS (8,10,12,13), we used the PCS of the SF-36 to assess health-related QOL in patients with MFS, and we evaluated the association of QOL with self-reported demographic factors, health behaviors, physical impairments, clinical characteristics, and MFS severity.
The development and design of the GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) registry have been previously described (14,15). Briefly, the GenTAC registry was created as a multicenter, longitudinal, observational cohort study of patients with aortic aneurysm and associated genetic conditions, including MFS. Patients were enrolled at 8 sites: Johns Hopkins University, Baylor College of Medicine, Oregon Health & Sciences University, University of Pennsylvania, University of Texas Health Science Center at Houston, Weill Cornell Medical College, National Institute of Aging-Harbor Hospital, and Queen’s Medical Center. Each site obtained Institutional Review Board approval, and each participant patient provided informed consent. Standardized data collection included patient questionnaires, imaging studies, and information about prior surgical procedures. The Research Triangle Institute International in Rockville, Maryland, served as the data coordinating center and was responsible for data management and statistical design and analysis (14,15).
We included patients in the GenTAC database who had MFS diagnosed by Ghent or revised Ghent criteria and confirmed by a core phenotyping laboratory at Johns Hopkins University (16,17), were age 18 years or older, and had completed the SF-36. We excluded patients <18 years of age both to be consistent with the existing literature on QOL in MFS and because parents could complete questionnaires for pediatric patients in the GenTAC registry. This study used de-identified survey data from the GenTAC registry. Patients were enrolled in the GenTAC registry from 2006 through December 31, 2013. The most recent analyses of our data were performed in September 2016.
SF-36 scale scoring
Our analyses focused on QOL, which was measured with the PCS of the SF-36 (18,19). The PCS comprises 4 subscales: physical functioning (PF); role limitations due to physical health (RP); bodily pain (BP); and general health (GH). Each score ranges from 0 to 100, and is standardized to the population norm of 50 with a SD of 10; higher scores indicate better QOL (18–20). Each of the 4 SF-36 subscales was standardized using a z-score transformation by subtracting the mean and SD from the 1998 general U.S. population. Composite PCS was computed using the score coefficients from the 1990 general U.S. population per the standard SF-36 scoring. The composite score is transformed to the norm-based scoring, where the norm is set as 50 with a SD of 10 (20).
Self-reported variables were extracted from the Clinical Evaluation Form and the Enrollment Patient Questionnaire. The Clinical Evaluation Form includes questions about enrollment diagnosis, age at diagnosis, number of prior surgeries, number of medications, or use of specific medications. For the Enrollment Patient Questionnaire, patients provided their date of birth and answered multiple choice questions about sex, race/ethnicity (white, black or African American, Asian, American Indian, Native Hawaiian, or Pacific Islander), education, marital status, household income, health insurance status (employer private health insurance plan, Medicare, Medicaid, other), employment (full time, part time, unable to work, student, homemaker, unemployed, and retired); health behaviors, including use of cigarettes, alcohol, and illicit drugs; and vision or hearing impairment. This form asks about 47 medical conditions, including the genetic conditions associated with thoracic aortic aneurysms (numbers 1 through 7); cardiovascular history including murmur, palpitation, angina, heart attack, cardiomyopathy and others (numbers 8 through 16); hypertension; stroke; aneurysms; cancer; diabetes; bleeding or clotting disease; gastrointestinal disease; arthritis; autoimmune diseases; joint dislocations; cognitive issues; and depression.
To evaluate QOL data in the presence of phenotypic variability, we created a clinical severity scale to differentiate mild, typical, and severe disease. Two scores have been created previously, but neither has been validated (21,22). For the score used in this paper, we included features of MFS that could be assessed on the basis of the self-reported data included in the questionnaires completed at GenTAC enrollment. We assigned points for features of MFS falling into 4 broad groups: skeletal, ocular, vascular, and “other.” Points for skeletal features were: scoliosis (1 point), scoliosis repair (3 points), pectus excavatum (1 point), pectus carinatum (1 point), pectus repair (2 points), and kyphosis or lordosis (1 point). Points for ocular features were lens dislocation (3 points), retinal detachment (2 points), early-onset glaucoma (2 points), and early-onset cataracts (2 points). Points for vascular features were enlarged aorta (1 point), dissection (4 points), mitral valve repair (3 points), aortic root replacement or valve surgery (3 points), and descending/thoracolumbar aortic repair (3 points). Points for other features included pneumothorax (1 point), migraines (1 point), and joint pain (1 point). Scores were graded as mild (0 to 2), typical (3 to 8), and severe (≥9). Relative scoring is similar to prior MFS severity scales. Also, similar to other MFS severity scales, prior surgery related to MFS increased severity to greater than mild, and ectopia lentis and aortic dissection each increase severity to greater than mild (21,22).
We used SAS software (version 9.4, SAS Institute, Cary, North Carolina) to extract data from the secure enterprise network database to create reports and summary tables, and to perform statistical analyses. To examine between-group differences, we used SAS PROC GLM to run solutions for Type III analysis of variance models and least squares mean estimates. The Tukey-Kramer test was used for post hoc pairwise comparisons for significant factors with 3 or more levels. For data security purposes, all analyses were performed and all data were stored in a password-protected remote workspace. We included variables that were significant in bivariate analysis (p ≤ 0.05) in a multifactor analysis of variance to identify those most strongly associated with QOL.
Of the 871 patients with MFS in the GenTAC registry, 643 were age ≥18 years, of whom 389 (60% of GenTAC MFS patients age 18 years or older) completed the PCS of the SF-36 (Table 1) and 254 did not. There was no difference between these 2 groups in sex or race, but the group that completed the SF-36 was older and had more severe MFS (Table 2).
Of the respondents who completed the SF-36, mean age was 41 years, one-half were women, and most self-identified as white. Most had some college education, one-third earned more than $100,000 annually, and nearly three-fourths had private health insurance. Scores for each subscale were PF 72.6 (or 45.6 with norm-based scoring), RP 46.2 (41.0), BP 65.9 (48.2), and GH 51.3 (41.2). Using norm-based scoring, the composite PCS was 42.3, within 1 SD from the population norm of 50.
In bivariate analysis (Table 3), better QOL, as indicated by higher scores across all 4 subscales and a higher PCS composite score, was associated with college education (PCS composite score 38.9 for education less than college vs. 44.3 for college graduates; p = 0.001), marital status (34.6 for divorced or separated, 42.0 for married or in a partnership, 44.3 for never married; p = 0.001), higher household income (35.7 for ≤$25,000, 42.0 for $25,001 to $100,000, and 44.2 for >$100,000; p < 0.0001), private insurance (33.7 for Medicare or Medicaid vs. 44.8 for private insurance; p < 0.0001), working as opposed to unable to work, unemployed, or retired (p < 0.0001), moderate alcohol use (38.5 for rare alcohol, 42.9 for near daily or daily, 45.1 for more than monthly, but less than daily; p < 0.0001), fewer comorbid medical conditions (46.7 for 0 to 2, 43.0 for 3 to 6, and 33.9 for ≥7; p < 0.0001), less severe MFS based on our scale (48.7 for mild, 44.6 for typical, 38.3 for severe; p < 0.0001), and absence of depression (44.0 if no depression vs. 36.8 if depressed; p < 0.0001).
Those unable to work due to disability had significantly lower scores on the PCS composite and each subscale, as compared with those who were retired, unemployed, or working. The working group scored highest on the composite and all subscales. Those unable to work due to disability also scored higher on the MFS severity score, had more MFS-related surgeries, and had more comorbid conditions (Table 4).
Four variables were associated with better QOL in the PCS composite, but not across all 4 subscales: younger age (score of 44.4 for ages 18 to 39 years vs. 40.4 for >40 years; p = 0.0022), with 2 subscales significant (PF and RP) and 2 subscales trending toward significant (BP with p = 0.0594 and GH p = 0.054); unimpaired hearing (43.0 vs. 36.8; p = 0.0052); nonsmokers (43.2 vs. 40.4; p = 0.046); and fewer prior surgeries (no surgeries 44.8, 1 or 2 surgeries 43.1, ≥3 surgeries 39.1; p = 0.002), with 3 subscales significant (PF p = 0.0012; BP p = 0.0084; and RP p = 0.04) and GH not significant (p = 0.06).
Sex, race, recreational drug use, vision impairment, use of beta-blockers, and use of angiotensin receptor blockers were not significantly different across the composite or any of the subscales.
In the multivariate model (Table 5), only private insurance status (p = 0.013) and employment (p < 0.0001) were associated with better QOL as assessed by the composite PCS (Central Illustration). In addition to the PCS score remaining significant, employment status also remained significant across all 4 subscales, whereas insurance status was only significant across the PF and RP subscales. Marital status (p = 0.057) and alcohol use (p = 0.053) were no longer significant.
Tukey-Kramer post hoc tests were performed on variables with ≥3 levels that were significant in the multivariate model. Although the post hoc test for income showed significant differences in the PF subscale between the 2 higher income groups ($25,000 to $100,000 and >$100,000; p = 0.02), the lower income group did not differ significantly from the other 2 categories. In the case of employment, QOL was significantly lower for those unable to work compared with the other employment categories, but there was no significant difference between the other groups.
In this largest study to date of QOL in adults with MFS, using the extensively validated SF-36, health-related QOL was 42.3, below the population norm of 50, but within 1 SD of the mean (18–20). The PCS composite score of 42.3 is better than scores seen in previous smaller studies of MFS patents (Table 6), including scores of 34.7 in Foran et al. (8) (22 patients with MFS) and 36 in Rand-Hendriksen et al. (12) (84 patients with MFS), but lower than the composite score of 45.5 in Schoormans et al.’s study (10) (121 patients with MFS). Despite small sample sizes, nearly all of the prior studies of MFS patients found a reduction in the PCS composite or in the 4 component subscales (5,8–10,12,13). Three of these studies used control groups derived from national datasets as comparators (8,10,12). Fusar-Poli et al. (9) found a reduction in the Mental Component Score, but not PCS, but their study was limited by a low response rate, with only 36 MFS patients enrolled from 380 families who were approached. When Lane et al. (6) looked at QOL in adults with congenital heart disease, only 6 of 276 patients had MFS, and so the authors could not comment about QOL in MFS. In a study of 174 MFS patients that assessed QOL with a different scale, the Ferrans and Powers Quality of Life Index, Cardiac Version III (QLI-Cardiac III) (7,23), QOL scores were low, but comparable, to those of adults with cardiovascular disease, whereas scores on the psychological/spiritual subscale were significantly lower than for cardiovascular disease (23).
In the current study, variables associated with worse QOL in the bivariate model were less education, being divorced (as opposed to married, in a partnership, or never married), lower household income, public health insurance (as opposed to private), and inability to work due to disability (as opposed to working, unemployed, or retired). Interestingly, MFS severity, number of MFS-related surgeries, and number of comorbid conditions did not impact QOL as independent variables. However, people who were unable to work due to disability were more likely to score in the severe range on the MFS severity score. Of that group, 56.9% had a score of severe MFS, whereas only 29.7% of those in other employment categories had severe MFS (p = 0.0002), to have had ≥3 surgeries (53.5% vs. 31.3%; p = 0.002), and to have ≥7 comorbid conditions (53.5% vs. 13.7%; p < 0.0001). This suggests that MFS patients in this study who were unable to work due to disability represent a category of patients with more severe disease.
Bathen et al. (24) looked at fatigue in 73 adults with MFS, and were surprised to find no correlation between fatigue and MFS-related health problems, such as aortic dissection or vision impairment. Instead, chronic pain and being unable to work (vs. employed or in school) were associated with increased fatigue. It is possible that those with chronic pain who were unable to work may also fall into this category of disability preventing employment.
In the Rand-Hendriksen et al. (12) study of 84 MFS patients, a low PCS composite and low subscale scores were not associated with any of the variables assessed, which included sex, body mass index, ascending aortic surgery, use of beta-blockers, visual acuity, joint hypermobility, or number of Ghent criteria fulfilled. In a study of 121 MFS patients, a low PCS and low subscale scores did not correlate with disease severity (10). Similarly, in a study of 857 MFS patients that used a nonvalidated questionnaire, 26.5% of the 857 respondents thought they were severely affected by MFS, which did not correlate with MFS severity (22). In semistructured interviews with 17 MFS patients, childhood teasing, concerns about physical appearance, and for women, concerns about childbearing impacted QOL (25). These features were unfortunately not captured by the GenTAC registry.
In the multivariate model, registry participants with private health insurance, compared with public health insurance, and those who were working or retired, compared with unable to work due to disability, had better QOL.
There was borderline significance to better QOL with more frequent alcohol use (p = 0.053) and with marital status (p = 0.057). The divorced or separated group had the lowest PCS composite score, and the lowest scores for 3 of the 4 subscales. The widowed group had the highest scores, but it is premature to draw any conclusions about the widowed group because it included only 5 patients (1.3% of study participants). Although being married would seem to be a surrogate marker for presence of social support, studies in patients with acute coronary syndromes (26), congestive heart failure (27), and colorectal cancer (28) show that being married or in a partnership does not necessarily connote social support, and the relationship between social support and QOL is not linear.
Having private health insurance has correlated with improved QOL in patient groups as diverse as pediatric patients with sickle cell disease (29), >5.7 million adults with arrhythmias (30), adult survivors of colorectal cancer (31), a predominantly black and Latino group of stroke survivors (32), and men with prostate cancer (33). Higher household income was not significantly associated with better QOL in our study, despite being associated with better QOL in a broad range of studies in non-MFS patients, including a nationwide sample of 2,700 American children (34), Chinese survivors of stroke (35), and lung cancer survivors (36).
Limitations of the current study include the use of registry data. There is the possibility of selection bias because only 60% of MFS patients in GenTAC who were age 18 years or older completed the questionnaire, although prior studies of QOL in MFS also had low response rates (9,11,22–24). Those who completed the SF-36 tended to be older than those who did not, and had more severe MFS: 41.7% of the completers had severe MFS, compared with 29.5% of those who did not complete the SF-36. As with all GenTAC studies, there may be differences between MFS patients that enroll in GenTAC and those who do not. GenTAC enrollees are seen at 1 of 8 major medical centers, which are referral centers for patients with genetic diseases that predispose to aortic aneurysms. Although patients seen at these centers may not reflect MFS patients seen at local centers, each site strives to recruit all eligible patients to GenTAC. There may be limits to generalizability because this population was predominantly white and well educated. Also, all variables were self-reported, although this has been previously validated.
In a large cohort of adults with MFS, health-related QOL was 42.3, below the population norm of 50, but within 1 SD of the mean. Registry participants with private health insurance, as opposed to public health insurance, and those who were working or retired, compared with unable to work due to disability, had better QOL. Notably, factors related to health and MFS severity did not correlate with better or worse QOL.
COMPETENCY IN SYSTEMS-BASED PRACTICE: Health-related quality of life in patients with Marfan syndrome is below the population norm and more closely associated with socioeconomic factors, specifically employment and medical insurance, than with disease severity or general health status.
TRANSLATIONAL OUTLOOK: Factors that influence quality of life should be considered in the design of clinical trials and systems of care to improve clinical outcomes for patients with Marfan syndrome.
The GenTAC registry has been supported by U.S. federal government contracts HHSN268200648199C and HHSN268201000048C from the National Heart, Lung, and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of the paper to disclose. Prof. Christopher A. Nienaber served as Guest Editor for this paper.
- Abbreviations and Acronyms
- bodily pain subscale
- general health subscale
- Marfan syndrome
- Physical Component Summary
- physical functioning subscale
- quality of life
- role limitations due to physical health subscale
- Medical Outcomes Study 36-Item Short-Form Health Survey
- Received November 2, 2016.
- Revision received March 30, 2017.
- Accepted April 4, 2017.
- 2017 American College of Cardiology Foundation
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