Description of the condition
Marfan's syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It was first discovered in 1896 by Professor Antoine-Bernard Marfan, a French paediatrician (Franken 2012; Judge 2005; Koracevic 2012). The condition is estimated to have an incidence of 1 in 2000 to 1 in 5000 individuals (Danyi 2012; Franken 2012; Von Kodolitsch 2007; Wright 2012).
Marfan's syndrome affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems (Castellano 2012; Pyeritz 2009). Aortic root dilation is the most frequent cardiovascular manifestation (Von Kodolitsch 2004), and its complications including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality in people with this disease (Canadas 2010; Franken 2012). One long-term survival study of Marfan's syndrome in the early 1970s showed the mean age of death to be 32 years for people who did not receive aortic surgery (Murdoch 1972).
Although other cardiovascular features such as valvular disease, endocarditis, cardiomyopathy and arrhythmias exist in these people with Marfan's syndrome (Pyeritz 2000; Von Kodolitsch 2004), dissection of the aorta has been, and remains, the most common cause of death (Pyeritz 2008; Silverman 1995). Aortic wall weakness, aortic dilation and arterial hypertension are the major mechanisms of dissection and rupture (Von Kodolitsch 2004). Research has shown that a defect in the FBN1 glycoprotein, a major constituent of the extracellular matrix microfibrils (Bunton 2001), leads to poor structural and functional integrity of the normal vessel wall by several potential mechanisms (Danyi 2011; Judge 2005; Von Kodolitsch 2007). The changes in the walls of the elastic arteries occur primarily in the medial layer and are associated with less distensibility and increased stiffness leading to consequent weakening and dilation, beginning in the sinuses of the aortic root and extending to the proximal ascending aorta (Pyeritz 2000; Pyeritz 2009).
Aortic root pathology has hence become the most important target for improving survival in people with Marfan's syndrome (Vaidyanathan 2008). As a result of improved diagnosis, careful monitoring, lifestyle guidance, medical and especially surgical management of this disease, the life expectancy of people with Marfan's syndrome has increased by at least 30 years (Pyeritz 2009; Silverman 1995). Although the benefits of prophylactic aortic surgery have been clearly demonstrated, the value of reducing aortic dilation medically is unclear in the clinical setting to reduce morbidity and mortality.
Description of the intervention
The primary aim of pharmacological therapy for Marfan's syndrome is to slow down the rate of aortic dilation with the goal to delay or prevent complications and surgical interventions (Franken 2012). The beta-blockade strategy began in 1971 when Halpern et al. suggested that the reduction of the rate of increase in aortic pressure over time was an important additional factor to lowering blood pressure alone in decreasing haemodynamic stress on the proximal aorta (Halpern 1971; Keane 2008; McKusick 2004). Beta-blockers became, and have remained, the standard preventive treatment since the mid-1990s when one randomised controlled trial (RCT) by Shores et al. concluded that prophylactic beta-adrenergic blockade with propranolol slowed the rate of aortic dilation and reduced the development of aortic complications in people with Marfan's syndrome (Shores 1994). Subsequent studies have shown varying results on the efficacy of beta-blockade therapy (Legget 1996; Rios 1999; Tierney 2007). Despite the lack of conclusive evidence, it has been recommended that people with Marfan's syndrome and aortic aneurysm should be prescribed beta-blockers to reduce the rate of dilation unless contraindicated (Hiratzka 2010; Keane 2008; Pyeritz 2012a; Wright 2012). Current beta-blockers in use include propranolol and atenolol. Atenolol is currently the drug of choice as it has a longer half-life and is more cardioselective than propranolol with fewer side effects (Keane 2008). The drug dosage is adjusted according to heart rate, aiming to maintain a rate of 60 to 70 beats/minute at rest and less than 100 beats/minute after sub-maximal exercise (Canadas 2010; Loeys 2010; Wright 2012). Beta-blockers have a significant side effect profile and documented adverse effects include bronchospasm, exercise intolerance, fatigue, depression, and first- and third-degree heart block (Gao 2011; Shores 1994).
Other anti-hypertensive medications such as calcium channel blockers, angiotensin-converting enzyme inhibitors and, more recently, angiotensin receptor blockers are suggested for people who are unable to tolerate beta-blockers or as an add-on therapy if beta-blockade monotherapy is unsuccessful at controlling blood pressure (Keane 2008; Wright 2012). Again, this suggestion is based on limited and conflicting data from relatively small studies (Rossi-Foulkes 1999; Topouchian 1998; Williams 2012; Yetman 2005), and trials are currently ongoing to determine their therapeutic effects and benefits further (Gambarin 2009; Keane 2008; Lacro 2007; Pyeritz 2012b).
How the intervention might work
Although the exact mechanism of beta-blockers in Marfan's syndrome is unknown, the potential benefits have been attributed to their negative inotropic and chronotropic effects, resulting in a reduction in aortic wall stress (Canadas 2010). This is important in decreasing the progression of aortic dilation as the degree of increase in aortic root diameter is a major indicator for the risk of dissection (Judge 2005). The anti-arrhythmic and anti-fibrillatory effects of beta-blockade are also believed to be advantageous as other cardiovascular manifestations such as mitral valve prolapse and left ventricular dilation are common in Marfan's syndrome, pre-disposing people to arrhythmias (Koracevic 2012).
The cardiac cycle is pulsatile in nature, with aortic expansion during systole and recoil during diastole. This pulsatile flow can be characterised by a change in pressure over time and contributes to the progression of aortic dissection compared with non-pulsatile flow (Castellano 2012; Liao 2010). The aorta buffers the level of fluctuation between the extreme pressures of systole and diastole, allowing a nearly continuous blood flow from the central to the peripheral vascular system (Belz 1995; Koracevic 2012). This protective function, known as the Windkessel effect, relies on the elasticity of the aorta (Belz 1995), and, as Marfan's syndrome, is associated with abnormal aortic elastic properties (Hirata 1991), people are therefore compromised. Studies have shown that beta-blocker therapy may directly affect the aortic wall by increasing its distensibility, and decreasing aortic stiffness and pulse-wave velocity (Groenink 1998; Ladouceur 2007; Rios 1999). With the favourable effects of beta-blockers on change in pressure over time, this pharmacological intervention became important in the medical management in aortic dissection (Castellano 2012; Danyi 2012; Liao 2010).
Why it is important to do this review
Beta-blockers have remained the standard treatment for the prevention of aortic complications since medical intervention was introduced in the 1970s. Studies investigating the efficacy and therapeutic benefit of beta-blockade have produced heterogeneous and conflicting results, leading to much debate on their life-long use for people with Marfan's syndrome (Ladouceur 2007; Moberg 2012; Tierney 2007). One meta-analysis by Gersony et al. in 2007 included six studies, of which only one was an RCT, and concluded that there was no evidence that beta-blocker therapy had clinical benefit in people with Marfan's syndrome (Gersony 2007). Conversely, Gao et al. concluded from their meta-analysis that routine prescription of beta-blockers may offer substantial benefit on clinical end points for children and adolescents with Marfan's syndrome (Gao 2011).
One Cochrane review on the medical treatment for small abdominal aortic aneurysms (AAA) reported that there was no significant difference in AAA expansion or cardiovascular end points between beta-blocker treatment and placebo. Furthermore, a significantly increased number of people discontinued beta-blocker therapy for AAA management due to adverse effects and there was a trend towards increased mortality with propranolol therapy (Rughani 2012). Although thoracic aortic aneurysms (TAA) are more common in Marfan's syndrome and extrapolating data from AAA to TAA studies should be conducted with caution (Castellano 2012), these findings do raise cause for concern.
Life-long treatment, as beta-blockade therapy in Marfan's syndrome currently remains, is not a decision or commitment that should be taken lightly. Even with the anticipation of new pharmacological treatments currently under trial, it is important to establish the efficacy of the baseline treatment that has been in place for decades. This would hopefully decrease the discrepancy gap between clinical practice and current evidence, and provide the physician with more options to optimise and individualise a management plan for his/her patient. Since aortic pathology is present in the vast majority of people with Marfan's syndrome and is the most life-threatening manifestation of this disease (Canadas 2010; Franken 2012; Gao 2011; Judge 2005), this review will focus on the effects of beta-blockers for preventing aortic dissection in Marfan's syndrome. Therefore, we will examine the most up-to-date literature to assess the long-term efficacy of this treatment in people of all ages with Marfan's syndrome and determine if current practice with life-long beta-blocker therapy is evidence based.