Marfan’s Syndrome and associated pathologies: An integrative systematic review of randomised controlled trials

Introduction

Marfan syndrome (MFS) is a hereditary disorder related to connective tissue with notable symptoms in the ophthalmic, skeletal, and cardiovascular systems. It is autosomal dominant and advances with age.¹ The estimated prevalence of MFS involve 1 per 4–6,000 population.² Acute aortic dissection, ectopia lentis (EL), aortic root (AoR) aneurysm, and disproportionate long bone overgrowth, are the main disorders connected to MFS. The disorder exhibits significant intrafamilial and interfamilial diversity and is extremely penetrant.³ Fibrillin-1, which is released and incorporated into the extracellular matrix, is known to be affected by senseless variations, insertions, deletions, and mutations connected to loss of expression from one allele in the FBN1 gene, which has been proven to induce MFS.⁴

The most evident systemic features in MFS include EL and skeletal abnormalities that mainly involve abnormal spine curvature (scoliosis), abnormally flexible joints, disproportionately long arms and legs, tall stature, and indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum.¹ Over the past 20 years, new traits connected to MFS have been discovered, including stretch marks (striae), a collapsed lung due to pneumothorax, expansion of the spinal canal of the lumbar region, and abnormally indented hip sockets. Additionally, aortic problems are also a defining characteristic of MFS patients.⁵ AoR growth, which is asymptomatic at first and increases over time to an aneurysm, is the first sign of thoracic aortic disease, which commonly affects MFS patients. Despite the fact that some drugs can slow growth, they cannot prevent it from forming.^1,5

Patients with MFS are susceptible to the potentially fatal cardiovascular consequences of aortic dissection and aortic aneurysms, thus early detection and effective management are crucial. The efficacy of current surgical and medical therapies for MFS patients with aortic disease has significantly increased mean life expectancy. As a result, the objective of this review is to compile and summate data on various medications that have clinical outcomes or can slow aortic dilatation rate between treatment groups, identify low-risk alternatives, and focusing on health-related quality of life, visual outcomes in lens subluxation surgery, and Adrenoceptor Beta 1 (ADRB1) genotyping in relation to medications.

Methods

This systematic review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.

Results

The search strategy described through the PRISMA flow diagram is illustrated in Figure 1.

Figure 1. Data extracted as per search strategy.

The quality assessment of the RCTs by using a modified version of the Jadad scale which consists of six items is described in Table 1.

Furthermore, the summary of the extracted data from the eight RCTs which analysed the different aspects of approach and presentation of MFS with its management options consisting of medical, psychological, and surgical interventions, related to various pathologies in MFS patients,is discussed in Table 2.

The parameters studied in this review involved comparative effectiveness of irbesartan, losartan, and atenolol medications for aortic complications, effective visual outcomes after Cionni MCTR for lens subluxation, results of ADRB1 genotyping as it is linked to atenolol response, and health-related quality of life (HRQOL) in MFS patients treated with atenolol and losartan; these demonstrated no significant difference between both groups but low health-related quality of life was observed in MFS patients.

Discussion

This review includes details on various medications that can slow aortic dilatation or have clinical events that differ between treatment groups, identifies low-risk substitutes, provides information on HRQOL, discusses visual outcomes in lens subluxation surgery, and discusses ADRB1 genotyping in relation to medications. Irbesartan treatment for MFS patients demonstrated a reduced rate of AoR dilatation when compared to placebo in a study presented by Mullen et al.,⁸ and was consistent with Groenink et al.’s findings that open label losartan had a positive effect on blood pressure over a three-year period of roughly 0.2 mm each year.¹⁶ Irbesartan has a half-life of 11 to 15 hours and higher antihypertensive effects than losartan, which has a half-life of six to nine hours.^17,18 The study demonstrates a reduction in the incidence of AoR dilatation in MFS patients receiving irbesartan throughout a five-year observation period.⁸ There were no differences in the adverse events assumed to be brought on by irbesartan side effects, and the medicine was well tolerated.

As such no significant results were observed between long-term treatment with losartan and atenolol in MFS patients. Even though it was not proven to be more effective in comparison to atenolol, losartan may be a substitute to β-blockers for long-term management.⁹ The four prospective RCT’s determined the effect of angiotensin receptor blockers (ARBs) in MFS patients. These studies showed that a modest decrease in AoR development rate at three years in the losartan-treated group was reported only by the COMPARE trial^{16,17,19–21} which was demonstrated in a meta-analysis as well.²² As β-blockers are considered for the conventional management; the limitation consisted of no control group with placebo.⁹

Patients with MFS exhibited worse overall physical and psychological HRQOL considering various components and age groups, according to a study presented by Handisides et al. In adults with MFS, a contrast of reduction in HRQOL have been observed ranging from none²³ to some associated investigations.^24–26 MFS had a considerable detrimental effect on HRQOL, according to a systematic review based on MFS patients.²⁷ Adults with MFS showed lower HRQOL, equivalent to those with other chronic illnesses and disabilities, according to Rand-Hendriksen et al.²⁸ In terms of social QOL, almost one in three persons with MFS reported feeling stigmatized or undervalued in society as a result of having MFS.¹⁰ Thus, for youth with MFS, HRQOL both socially and psychologically can be worse during these years of middle and high school, with the possibility of having a significant detrimental influence on basic emotions, well-being and self-worth as well as on social and academic performance.

Lens subluxation in MFS is a common pathology and applying MCTR during surgery led to an improvement in best corrected visual acuity, demonstrating it to be a safe option.¹¹ The main objective in cases of lens subluxation is to surgically treat lenticular astigmatism as effectively as possible.²⁹ In MFS patients, executing lens extraction along with pars plana vitreolensectomy may be difficult and exacerbated by the loss of the capsular bag, endothelial cell destruction and vitreous disruption when the lens loses a considerable amount of zonular support.¹¹ In the presence of advancing zonular deterioration, MCTR can adequately maintain and rectify capsular bag decentration. With less trauma and more ease, MCTR can be implanted into capsule bags. It can also be simply fixed to the sclera with one or two sutures without compromising the quality of the capsular bag. There have also been reports of additional benefits of MCTR implantation, including reduced vitreous loss and the ability for posterior chamber intraocular lens (PC-IOLs) implantation in capsular bags.³⁰ Furthermore, the post-operative consequences such as glaucoma, retinal detachment, and intraocular lens displacement can also be decreased.^11,31 The MCTR can be used for lens subluxation since it has been proven to be a great tool for delivering better stability with zonular dialysis of capsular bags.

Moreover, a study by Van Driest et al. examined whether variations in the CYP2C9 and ADRB1 genes reveal subgroups of people who respond differently to treatment for MFS and found that ADRB1-rs1801253 was connected to atenolol response in MFS patients.¹² The results of the study demonstrate the clinical potential of pharmacogenomics by showing that a subset of people for whom atenolol may be more advantageous than losartan is identified by a genetic biomarker. rs1801253 CC has been linked in earlier studies to higher beta-blockade-induced heart rate decrease.³² Heart rate cannot be the only reliable measure of β-blocker action when the aim is to stop progressive aortic dilatation. The possibility can be that atenolol has an impact irrespective of the heart rate. This may help to explain why the CC genotype showed a larger improvement in AoR z-score (AoRz). Future studies concentrating on this investigation are necessary due to this limitation.¹² Therefore, the rs1801253 variant may be able to identify a subset of patients who would benefit more from atenolol treatment in comparison to losartan. If differences in medication responsiveness by genotype are replicated and demonstrated to be clinically relevant, the ADRB1 test may be used to identify individuals who are more likely to respond therapeutically to atenolol than to losartan.

Similar to this, a study found independent predictors of the rate of AoR dilatation and referral for aortic surgery. The AoR dilatation cut-points that signal a recommendation for aortic surgery were shown to have high specificity but low sensitivity. Larger prior studies showed that AoR dimensions at baseline were related to subsequent AoR dilatation in MFS. Baseline AoR diameter was the primary predictor for progressing aortic root dilatation in 78 people with MFS (aged 18 to 50 years) with a median echocardiography follow-up of 71 months. This was found in 19 MFS children (aged 1 to 18) AoRz> 2 at baseline who underwent monitoring through echocardiography for up to eight years.^13,33 Since in younger individuals AoR develops concurrently with more advanced somatic growth, children with MFS throughout their childhood tend to keep similar AoRz. Since their AoR continues to increase as they age, older people with MFS typically have growing AoRz, but once somatic growth is completed, their body surface area becomes stable. In contrast, AoR diameter with MFS tends to expand across all age groups.¹³ The effacement of the sinotubular junction, which is defined as expansion of the dimension of the junction in relation to the ascending aortic dimension or AoR, implied that measuring the dimensions of the junction could provide a further helpful indicator of AoR dilatation that occurs more quickly, both clinically and in future research. The maximum sinotubular junction diameter, however, was with the highest inter-observer variability, according to data from the trial that had previously been reported.³⁴ Therefore, merely detecting sinotubular junction effacement rather than actually measuring its size through echocardiography may be more beneficial.

Van Andel et al. carried out a study into the clinical results of losartan in patients with MFS for the long-term and reported that effective clinical benefits of losartan with an average follow-up duration of eight years.³⁵ Additionally, for beneficial effects, losartan and β-blockers should be given in combination. During a three-year follow-up period, the initial COMPARE trial found a minor but significant benefit of losartan medication on the rate of AoR dilatation in people with MFS. Other RCTs carried out globally, however, failed to demonstrate this benefit, raising questions about the effectiveness of ARBs and β-blockers. Short follow-up periods and low aortic dilatation rates may be the reason for ARB's lacking superior impact over β-blockers.^14,20 With an average follow-up of 6.7±1.5 years, the LOAT (LOsartan versus ATenolol) study authors could not find relevant results between both the groups in terms of AoR development or clinical events, but favorable effect of losartan over atenolol was observed.⁹ This supports the idea that people with MFS might benefit from treatment that combines losartan and β-blockers.

Tierney et al. discovered that despite no discernible difference in the rates of AoR growth, atenolol therapy decreased the heart rate-corrected AoR stiffness index (SI) over a three-year follow-up in comparison to losartan. It was hypothesized that this was because β-blockers use has adverse inotropic effects, which lower the peak shear stress in the aorta and lessen the impulse for dilatation.¹⁵ Losartan lacks this possible advantage because it does not have this adverse inotropic effect. Recent research by Prakash et al. on 83 patients with connective tissue illnesses, including MFS, showed a strong correlation between higher rates of AoR dilatation, higher aortic stiffness, and surgical aortic replacement as measured by MRI.³⁶ These investigations show that aortic stiffness assessed by echocardiography or MRI may be used to identify patients who are more likely to experience rapid AoR dilatation and unfavorable clinical outcomes, potentially enabling appropriate monitoring and diagnosis and more adequate management. Additionally, those with above-median AoR Elastic modulus (EM) and a high AoRz may be at a heightened risk of unfavorable consequences. Echocardiography makes it simple to evaluate EM and SI, which means they might theoretically be used in routine clinical surveillance for MFS patients. Further research is required to confirm non-invasive aortic stiffness measurements for risk classification. As a result, atenolol lowered the AoR SI more positively than losartan, indicating that atenolol (or combination of losartan and atenolol) medication may be desirable in individuals with higher aortic stiffness.¹⁵

According to Depping et al.'s evaluation of peer counselling and self-management intervention along with care as usual (CAU) versus control group employing CAU alone; acceptance can improve mental health and raise quality of life.^37,38 The treatment of a large patient population made up of numerous frequently ignored subgroups can be improved by placing more emphasis on shared experiences and emotional outcomes.

Conclusions

This review highlighted the management of MFS related to various pathologies and concluded that the combination of atenolol a β-blocker and losartan, which is an ARB, is beneficial in case of AoR dilatation and higher AoR stiffness in MFS patients. Additionally, people who are more likely to respond therapeutically to atenolol than to losartan may be identified by ADRB1 testing. In lens subluxation, MCTR is considered as a beneficial tool for stabilizing capsular bags.

Furthermore, due to the significant negative effects on academic performance, social functioning, and general emotions of self-worth and wellbeing, young adults with MFS are likely to have worse psychosocial HRQOL during their school years. Additional research exploring the FBN1 haploinsufficient genotype-phenotype connection with ARB therapy response will undoubtedly offer new insights and viable treatment choices as genetic testing becomes more widely used in diagnosis and classification. Future studies focussing on RCTs with respect to various management options along with follow-up outcomes related to various pathologies in MFS should be employed to enhance patient’s health related quality of life.