1.1 Hereditary thoracic aortic aneurysm and dissection

Hereditary thoracic aortic aneurysm and dissection (HTAAD) is a group of rare hereditary conditions affecting the aorta and other major arteries.1-3 The most common conditions include Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos syndrome (vEDS).2, 3 HTAAD diagnoses may affect many organ systems; including the cardiovascular, musculoskeletal, craniofacial and ocular system and cutaneous features.2, 3 An extensive list of human genes and clinical implications associated with HTAAD are described in several papers. To date, 30 genes have been found to be associated with HTAAD.3

The most serious complications in HTAAD diagnoses are related to the cardiovascular system, with risk of aneurysm and dissection of the aorta and other large arteries.2, 4 Life-threatening complications can require emergency intervention without prior warning, with increased risk of subsequent morbidity and potential loss of physical function.1, 5, 6 The autosomal-dominant mode of inheritance can cause anxiety about pregnancy for the patient's own health and the health of their children. Being diagnosed with an HTAAD diagnosis and getting acquainted with the consequences for themselves and their children may be experienced as a shock and life crisis. Because of the risk of aortic dissection many patients are advised to refrain from contact sports, to limit their physical exertion and strict blood pressure control.1, 7 Unfortunately, for some followed by inactivity and a sedentary lifestyle. The chronic pain, fatigue and physical impairment associated with HTAAD diagnoses1, 8-13 may be exacerbated by the fact that research is limited and that most of the HTAAD diagnoses have no effective treatment or cure.2 Living with an HTAAD diagnosis may be vastly more complex than its medical features. Any aspects of an individual's life may be affected. One systematic review of psychosocial aspects of MFS published in 2015 identified a total of five articles dealing with QoL in MFS.11 This review11 found that having a lifelong, potentially disabling disease with the possible affection of many different organ systems may cause increased challenges in daily life, psychosocial distress and decreased QoL.

1.2 The rationale for the review in the context of what is already known

In recent years, QoL has increasingly been studied in genetic conditions and recognized as an important element of clinical decision making.14, 15 Although health providers strive to promote patients well-being, a problem is that the term QoL refers to a variety of related conceptually distinct decisions/understandings.16 Authors often do not explicitly define QoL, but rather imply its meaning by the constructs measured.14 Other similar terms used in the literature of QoL are “satisfaction with life,” “well-being,” “life-satisfaction,” “health-related quality of life” (HRQoL) and “life-happiness.”17-20 There is a wealth of distinct and discrepant scales created to measure QoL both generic and disease-specific, but to the best of our knowledge no disease-specific scales have been developed to measure QoL in HTAAD diagnoses. Moreover, factors that contribute to positive QoL and greater adaptation to life are largely unexamined. Facilitating adaptation to the medical, physical, and psychosocial implication of the condition is a fundamental goal of genetic counseling14 and improving QoL should be one of the most important goals of any health care intervention or multidisciplinary approach.21

Figure 1 describes how the complexity of the diagnoses and daily life aspects may influence QoL for patients with HTAAD diagnoses.

The aim of this systematic review is 4-fold: (a) to identify publications of QoL in patients with HTAAD diagnoses, (b) to critically appraise the existing literature, (c) analyze and synthesize what the research shows about QoL in these patient groups including clarifying key concepts and identify knowledge gaps (d) discuss clinical implications and directions for future research on QoL in HTAAD diagnoses.

2.1 Study design

Owing to the limited number of studies of QoL in HTAAD diagnoses, all studies where at least one primary aim was to study QoL in HTAAD diagnoses were included in the review protocol. The study was conducted according to the recommendation for systematic reviews22, 23 and quality assessment for the type of studies included in the review.24-29 Each study was examined independently, and standardized criteria were used to critically appraise the different types of studies.26, 27 In the assessment of the included articles, only the QoL part of each study has been focused. The results were compared across the studies, to uncover and discuss the degree of concordance and discrepancy between reported QoL in the different diagnoses in the included studies.

2.2 Search strategy

Systematic searches were conducted in PubMed, Cochrane, Cinahl, Eric, Google Scholar and Web of Science (literature from 1990 to 20th of October 2018). The following search terms were used: heritable thoracic aortic aneurysm dissection OR familiar thoracic aortic aneurysm dissection OR thoracic aortic aneurysm dissection OR genetic aortic disease OR MFS OR LDS OR vEDS OR EDS Or Rienhoff OR arterial tortuosity OR dissection OR aneurysm OR osteoarthritis syndrome OR HTAAD OR FTAAD OR TAAD OR the terms all 30 genes associated with HTAAD3 (14 982 hits). Another search was carried out in the same databases with the terms and operators related to Quality of life (QoL)15-19 with the following terms and operators: Health-related quality of life OR Quality of life OR HRQoL OR QoL OR SF-36 OR life satisfaction OR psychosocial OR psychological OR psychiatric OR social-emotional functioning OR emotional-well-being OR satisfaction with life OR life satisfaction OR well-being OR life happiness OR mental health (a total of 903 708 hits). Search 1 combined (AND) with search 2 resulted in 225 hits (after deleting duplicates and foreign language articles [ex. Japanese]). Additional references were sought by examining the citations in papers that were obtained through the specific searches. A secondary search was performed of the Open Gray database and the International Clinical Trials Registry Platform, and 13 articles were found. Experts in the field were asked for additional publications, but no additional papers were found.

2.3 Eligibility criteria

The basic criteria were developed based on preliminary review of a random subset of relevant QoL studies and informed by conceptual and theoretical literature.

The three basic inclusion criteria (Table 1) were: (a) individuals affected with a specific HTAAD diagnosis. HTAAD were defined as diagnoses/genes associated to HTAAD.1, 3

Studies with mixed populations including HTAAD diagnoses that did not report subgroup analyses were excluded. (b) All types of studies, peer-reviewed papers presenting own results, published in English, German, French or Scandinavian language were included. (c) The third inclusion related to the purpose of the study “at least one primary aim was to describe QoL and/or predictor variables or factors associated with QoL in HTAAD conditions.”. A “Quality of life study” was defined as a study in which QoL, consistent with the previously described conceptual definition of the construct, was measured as a primary outcome variable using a validated, multi-dimensional scale, or measured by qualitative approach. No exclusions were made on the basis of age, gender or ethnicity. Unpublished data and case-report studies with less than four participants were excluded.

Two reviewers (G.V. and J.E.W.) independently reviewed the abstract from each citation that was identified through the search strategy described above. When considered potentially eligible, the complete text of these studies was obtained and reviewed by the same two reviewers (G.V. and J.E.W.). Two other reviewers (T.B. and H.J.) reexamined the included articles against the eligibility criteria. Then a fifth reviewer (A.Ø.G.) verified the article inclusions or exclusions and did the final assessment against the eligibility criteria.

2.4 Handling data, critical appraisal and data extraction

All included papers were screened and categorized independently by four reviewers (G.V., J.E.W., T.B. and H.J.) on the basis of the content in the articles.26, 30, 31 Discrepancy and disagreement were discussed and resolved by involving a fifth reviewer (A.Ø.G). The studies were first categorized into which HTAAD diagnoses the study dealt with. Specific criteria were used to critically appraise each paper.26, 28, 30, 32 Seven criteria were evaluated: (a) study design, (b) sample representativeness, (c) control group, (d) validity of measurement, (e) droupout/missing data, (f) blindness, and (g) credibility assessment.25, 26 No controlled trials or randomized controlled trials (RCT) studies were found therefore the criterion 6 about blindness was superfluous and omitted. Instead, we added a criteria “to which degree the papers discussed the limitations of the study” (criterion 6). In addition to these seven criteria, we also added a criterion “to which extend the paper contributed to new knowledge of QoL in HTAAD” (criteria 8). Because of the complicated diagnostic process of HTAAD diagnoses, we registered information from the included papers on the use of diagnostic criteria or/and genetic testing to identify the study population. This is highly important when it comes to the assessment of representativeness and generalizability of results. The studies were too heterogeneous to perform statistical pooling. Therefore, a narrative synthesis of the findings was performed, taking into account methodological quality and analytic rigor in the examination of the reported findings.29, 33

Information was extracted on: study population, diagnosis, recruitment source, study design, QoL measurement, key predictor variables, main results and author conclusions. Each study was analyzed for the primary outcome of QoL. A thematic analysis was conducted to structure and depict all the variables involved in the reviewed studies. A matrix was used for summarizing and synthesizing the results from the different studies. Issues of interest were: statistical comparison with healthy controls/population norms or other diseases; analysis of associations with related health problems and psychosocial predictor variables. This approach was used to integrate the conclusions from the results of the papers (comparing, contrasting, building on, or embedding with other) to provide a better understanding of QoL in HTAAD. Finally, the results of the articles were synthesized and summarized in three different main themes: “QoL in adults with an HTAAD diagnosis compared to other groups”, “Predictors of QoL in HTAAD patients” and “QoL in pediatric patients with HTAAD.”

3.1 Search results

The search strategy is presented in the flow chart in Figure 2. A total of 227 papers were identified, and 20 satisfied the eligibility criteria and were included in this review.

3.2 QoL in HTAAD-diagnoses

The included studies were all on MFS, none studies of QoL in vEDS, LDS or other HTAAD were found. One small study included both patients with MFS and EDS, but did not report separate results vEDS. Therefore, the results of EDS were omitted from the present review. Because of the total lack of research on QoL in other HTAAD diagnoses than MFS, this review mainly deal with research on QoL in MFS. Of the 20 studies, three studies dealt with children with MFS (Figure 2).

3.3 Methodological appraisal

3.4 Synthesizing and summarizing the results of included studies

3.4.1 Quality of life in adults with HTAAD diagnoses compared to other groups

Twelve studies 9, 35-37, 39, 44, 47-49, 51-53 found decreased QoL in MFS compared to general population (GP), but the results were divergent and conflicting. Figure 3 shows a comparison of the results from the 12 papers using SF-36 or SF-12 of the 17 papers of adults with MFS. Figure 3 is somewhat incomplete as the studies vary in ways they present the results. Two studies9, 44 found decreased QoL in all subscales of SF-36 compared to GPs. Four studies37, 48, 51, 53 found decreased QoL only in the physical component score (PCS) of SF-36 or SF-12 (Figure 3).

One study found decreased QoL only on the mental component score (MCS) of SF-36,36 which is in accordance with a study35 using QLI-cardiac also found decreased QoL only on the spiritual/psychological domain.

Compared to other diagnoses one study9 found that patients with MFS had lower QoL compared to patients with hypertrophic cardiomyopathy, cystic fibrosis, Behcets syndrome another study39found that patients with MFS had similar or higher QoL compared with patients with Tourette syndrome, systemic lupus erythematosus, multiple sclerosis, Parkinson disease and psychiatric disorders.

4.1 Research on QoL in the different HTAAD diagnoses

In line with the first aim, this systematic review identified 20 papers presenting QoL in HTAAD diagnoses. All studies dealt with MFS. Most of these studies were published during the past 3 years. This indicates that the interest for studies on QoL in MFS has increased, but studies of other HTAAD diagnoses are still lacking. There may be several reasons for this. Despite that, the prevalence of the different HTAAD diagnoses is poorly described it is assumed that MFS is more common and well-known than the other HTAAD diagnoses. The prevalence of MFS (10/100 000)59, 60 is higher compared to LDS (2/100 000)61 and vEDS (0.5- 2/100 000).62 The prevalence of the other HTAAD diagnoses is even rarer. Over the prior two decades there has been exponential increase in genetic research on the mutations explaining the HTAADs.3 The intense focus on diagnostics, survival and treatment may have deflected clinical attention from patient's complaints and QoL. LDS is a relatively new diagnosis, first described in 2005,2, 63 so most studies of this patient group probably concerns medical aspects of the diagnosis. VEDS is one of 13 subtypes of EDS, and no studies were found reporting subgroup analyses of QoL in vEDS. Because of the most of the symptoms of MFS are overlapping with the symptoms of LDS, vEDS and other HTAAD diagnoses; it is probably that factors affecting QoL in patients of MFS also affect QoL in other HTAAD diagnoses.

4.2 Critical appraisal of the literature

The second aim was to critically appraise the found literature. No studies had a qualitative design. The studies of QoL in MFS were limited in size, and the overall methodological quality of them ranged from good to fair. The main findings were that the identified articles and the results consistently were based on small sample sizes and/or low response rate. All reviewed studies were cross-sectional quantitative studies except one small pilot intervention study. No RCT or controlled trials were found. The respondents in most studies were recruited from the Marfan Foundations or hospital where the researchers worked. These strategies yield a risk for bias of recruiting motivated persons of groups with particular problems. Thus, the data collected may be different from the non-respondents and represent a bias when it comes to the total population. The patient population mainly derived from Western countries except one from Korea,52 which limits the generalizability of these findings. Cross-cultural differences in QoL are found in several studies.64

The results from our review show that nearly all studies used standardized instruments with generic scales design. Twelve of the 17 studies in adults with MFS used SF-36 or SF-12. These instruments can provide quantitative indication of an individual's health status and are the most widely-used QOL evaluation tools in the world. A problem was that several of the included studies in our review incompletely reported the results of SF-36 and SF-12, so it was not possible to perform meta-analyses or statistical pooling of these results. Such meta-analyses could have been useful for clinical practice and further research. None of the studies in this review discussed the appropriateness and suitability of SF-36 for measuring QoL in patients with genetic aortic disease. Despite that most studies underlined that the SF-36 was validated for other patient groups, it has not been evaluated in HTAAD diagnoses. Only one study35 used diagnose specific scales for patients with cardiovascular conditions. More recently, disease-specific scales have been developed for a number of health conditions, including a few genetic conditions, such as cystic fibrosis and sickle cell anemia,14 but not for HTAAD diagnoses. One of the included studies Moon et al52 suggests that follow-up studies should be performed to develop and apply a disease-specific QoL tool for patients with MFS. Another possibility might be to develop specific scales for measuring QoL related to potential direct effects of an HTAAD diagnosis and for evaluating outcome of clinical trials.

Despite that several studies used the same instrument for measuring QoL, the results from the studies were contradictory, but this may reflect differences in study design, recruiting routines and methodological and national differences in perception or communication of QoL. The representativeness and the generalizability of the studies might be questioned. However, strength was that several studies emphasized to describe and discuss the limitations of their studies. This, in turn, might contribute to better credibility of the study.

4.3 Synthesizing the results of QoL in HTAAD

Aim 3 was to identify and synthesize the main results from the reviewed studies. Only QoL studies in MFS was identified and a total of 2563 persons (Table 2) with verified or self-reported MFS diagnosis have been examined in the reviewed studies. The results from the reviewed papers are equivalent when indicating that adults with MFS have vastly lower QoL than the general population; indicating that individuals with MFS may experience a significant impact of their diagnosis regarding QoL. This is in accordance with at a study of Lane et al65 assessing QoL in a large group of patients' growing-up with congenital heart disease (GUCH) by using SF-36, showing decreased QOL in comparison with an age- and gender-matched general population.

Several studies9, 35, 37, 39, 52 hypothesized that the biomedical aspects of MFS such as aortic and visual symptoms may have great impact on QoL, but only a few studies found such associations. Studies9, 35, 39, 46 rather indicated that the subjective perception of MFS may have substantial impact on QoL. The physical severity of the diagnosis can be discussed,9 but in most of the papers, severity appears to be mainly associated with the disease's cardiovascular manifestations.9, 35, 39, 66 The cardiovascular manifestations may be underestimated both by adults and children as long as no individuals experienced subjective complaints. The subjective severity appears to be mainly determined by manifestations that is perceived by the patients or that causes physical disability.66 The differences between the physical severity and subjective severity indicate that the patients perceive the disorders differently from the professionals. This is important for healthcare providers to recognize when discussing patient-reported symptoms and possible impact on QOL in clinical practice.

Some of the included studies found that demographic factors, such as increased age, low educational level, not working and low-income decrease QoL. This is similar to findings in studies of other diagnoses67-70 and those of the general population This might indicate that the health condition is often reflected in poorer QOL, but sometimes it might be difficult and probably impossible to separate “cannot work” from “very sick.”71 Although one's health may influence QoL, it cannot be solely explained by the diagnosis. QoL is not representative of health per see, the concept in its truest sense represent the global perception of wellbeing. According to Pepper et al71 individuals with a genetic cardiovascular disease usually are well informed about their illness, but they are also extremely worried. Having a lifelong, potentially disabling disease with the possible affection of many different organ systems may cause increased challenges in daily life, decreased QoL and psychological distress.9, 35

4.4 Clinical implications for health care providers

Our fourth aim was to discuss clinical implications and direction for future research on QoL in HTAAD diagnoses, including clarifying key concepts and identify knowledge gaps.

Drawing general conclusions about the results of this review were difficult, primarily because the studies employed a variety of methodologies, and the methodologies were not always adequately described. Despite these limitations, most of the reviewed studies find that QoL in adults and children with MFS are decreased and that the subjective perception of the diagnoses may be an important predictor of QoL. There is a lack of and need for research on QoL in other HTAAD diagnoses. The goal of the next frontier in healthcare for individuals living with HTAAD diagnoses may be to improve QoL, not only by advancement in medical treatment, but also with interventions aimed at modifying psychosocial and contextual factors that influence QoL. Patient-reported QoL should be incorporated into clinical practice to ensure the patient's perspective is included in clinical decision making.46 Because a HTAAD condition affects every aspects of their daily life, interventions aimed at enhancing QoL by adjusting psychosocial factors need to be designed and tested. Intervention might aim to adjust appraisal of the stress evoked by the threat of the condition.39

4.5 Direction for future research in HTAAD

There is a great need for further studies on HTAAD diagnoses that will aim to advance our understanding of QoL, both as a concept and as an important outcome. The importance of conceptual clarity, rigorous methodology with appropriate QoL scales and theoretically grounded research must be emphasized. Then, the research will yield more evidence-based research relevant for clinical applications and intervention to facilitate improvement in the healthcare and counseling for individuals living with HTAAD diagnoses, and thereby enhance patients' QoL. Although only quantitative research was identified in this review, qualitative studies into QoL can also yield rich data. Qualitative data may also be important supplement to quantitative data. Using a mixed methods approach, with combination of qualitative and quantitative design is recommended. This may give a more complete understanding of how the patients may perceive QoL in different context and which factors are important for increasing QoL. Further research is required to better understand the potential importance of QoL in HTAAD, which will affect the organization and content of the assessment and management of children, adolescents and adults with HTAAD. The assessment of QoL in patients with HTAAD diagnoses should also be further explored in other cultures and geographical regions, including Eastern Europe, South America, Asia, Africa and Australia. It is a challenge to conduct studies on rare disorders, because of small sample sizes. International collaborative studies, using the same study design and disease-specific QoL measurements and only including people with genetically verified diagnoses are recommended. This might contribute to better understanding of how the diagnoses and health symptoms may influence QoL in HTAAD patients, also across diverse cultural differences. To achieve better knowledge, internationally researcher can cooperate on developing a disease-specific scale for measuring QoL for patients with a genetic cardiovascular condition. Disease-specific measures would be more responsive and clinically useful, and will give a more exact picture of how the diagnoses impact QoL across different cultures and context.

4.6 Limitations and strength

Only literatures written in English, German, French and Scandinavian language were included in this review. This might be a limitation, however, no studies written in other language were found with English abstract. Another limitation may be that we have not included case-report studies with less than four participants, but no such studies which met the other inclusion criteria were found. Choice of search words and our cultural and conceptual understanding may have limited our identification of papers and the interpretation of the content of the included studies. A strength is that we used updated information on selecting search words, both for HTAAD and QoL. Another strength might be the use of authorized criteria for critically appraising the studies. Four reviewers with the supervision from the fifth reviewer independently selected the studies, critically appraised and categorized the results from the different studies to ensure the quality of this process. Disagreement and contradictions were solved through discussion and new review of the relevant articles.