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Marfan syndrome (MFS), named after Antonine-Bernard Marfan, Professor of Pediatrics in Paris, is classified as an autosomal dominant hereditary connective tissue disorder caused by defects in the gene encoding fibrillin-1, which is essential for the formation of elastic fibers and microfibrils. Fibrillin is most abundant in the connective tissue surrounding the aorta, eyes, lungs, and bones. The first documented case of MFS was in Paris in 1896 when a five-year-old girl was described as having disproportionately long, thin limbs and digits, fibrous contractures of the fingers and knees, a long and narrow skull, tall stature, displacement of the lens, malfunction of the mitral valve, and thoracolumbar kyphoscoliosis (Pyeritz 2000). The involvement of the aorta was not described until 1943 and the extent of cardiovascular involvement was not documented until 1955. In 1991, H.C. Dietz determined that the mutation of the gene FBN1 accounted for Marfan syndrome. FBN1 is responsible for encoding the glycoprotein fibrillin-1 and is a major component of the extracellular microfibril. Pleiotropism in different organs is on the rise in MFS patients because the affected individuals are living longer. Underlying connective tissue abnormalities appear in mid-to-late adulthood.
The major criteria of the skeletal system for the diagnosis of MFS are: pectus carinatum (protrusion of the sternum), pectus excavatum (a caved-in or sunken appearance of the chest) requiring surgery, reduced upper to lower segment ratio or arm span to height ratio (>1.05), positive wrist and thumb signs, scoliosis of greater than 20 degrees, reduced extension of the elbows (< 170 degrees), medial displacement of the medial malleolus causing pes planus (the collapse of the arch in the foot), and the protrusion of the acetabulum. The presence of four major skeletal manifestations is required for MFS. The major criteria of the cardiovascular system for the diagnosis of MFS are the dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva or the dissection of the ascending aorta. Minor criteria involving the cardiovascular system are: mitral valve prolapse with or without regurgitation, dilatation of main pulmonary artery in the absence of valvular or peripheral pulmonic stenosis below the age of 40 years, calcification of the mitral annulus (the fibrous ring surrounding the mitral valve) below the age of 40 years, or dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years. The pulmonary system includes spontaneous pneumothorax (collapsed lung) or apical blebs (Pyeritz 2000). Major criteria in at least two different organ systems and the involvement of a third organ system are required for MFS.
The major cause of morbidity and premature death in MFS is due to aortic root dilation and associated regurgitation, dissection, and rupture (Jondeau et al., 1999). This is due to abnormal elastic fibers and decreased cross-linking of elastin receiving a steady stress from pulsatile pressure. A major determinant of the ascending aorta dilation in MFS is the central pulse pressure. This was experimentally proven by performing a noninvasive test on twenty patients, ages 17 to 61 years old, all of whom fulfilled the criteria for MFS. Six patients had mild aortic regurgitation and eight patients had mild mitral regurgitation. Six patients were receiving ¢-blocker medication up until the day before the experiment. The other fourteen patients were not receiving any medications. The control group consisted of twenty age- and sex-matched normal subjects. Echocardiographic examination was used to measure the diameter of the aortic root, including the annulus, sinuses of Valsalva, and the supra-aortic ridge at end diastole. Common carotid artery, common femoral artery, abdominal artery, and radial artery pressure waveforms were also recorded. Arterial compliance and distensibility were estimated through changes in arterial cross-sectional area and blood pressure during systole (Jondeau et al., 1999).
In MFS patients, the ascending aorta was significantly larger than the control subjects at the sinuses of Valsalva. The left ventricular diameter during systole or diastole and left ventricular mean wall thickness were not significantly different between MFS patients and the control subjects. The diameters of the common carotid artery, the common femoral artery, and the radial artery did not statistically differ between the two groups. However, absolute and relative stroke changes in the abdominal aorta diameter were lower in patients with MFS than those in the control group. The cross-sectional distensibility of the abdominal artery was lower in MFS patients as well. The groups did not statistically differ in the absolute and relative stroke changes in the common carotid artery, the common femoral artery, or the radial artery. The two groups also did not statistically differ in the distensibility and compliance of the common carotid artery, the common femoral artery, and the radial artery. The only pulse pressure that statistically differed between the two groups was the carotid pulse pressure, which was significantly correlated with the radial pulse pressure in both groups. The ascending aorta diameter was positively associated with radial pulse pressure in MFS patients and negatively associated with the control group, suggesting that carotid pulse pressure was a good predictor of dilation of the ascending aorta in MFS patients (Jondeau et al., 1999).
MFS patients statistically have a larger diameter of the ascending aorta than those not suffering from MFS and this difference is accounted for by the change in carotid pulse pressure, which is influenced by the geometry and stiffness of the aorta. The aortic dilation may be due to the mechanical breakdown by hemodynamic stress of the elastic fibers found in the aorta. This study also showed that the cyclic stress of the pulse pressure, which is dependent on the number of cycles and amplitude of stress, is a more important determinant of an enlarged aorta than the steady stress of blood pressure. MFS patients face an increase in arterial stiffness of the aorta and those with a high carotid pulse pressure are at a high risk of ascending aorta dilation. Since carotid pulse pressure is positively correlated with an increase in ascending artery diameter, it could be a useful tool for evaluating the risk of developing MFS.
Echocardiographic studies have shown cardiac abnormalities in MFS patients such as aortic root enlargement and mitral valve prolapse, leading to an abnormal backflow of blood from the left ventricle into the left atrium. The appearance of mitral valve prolapse seems to occur equally between children and adults of the same sex. MFS patients could also face aortic regurgitation in which blood flows back into the left ventricle from the aorta during diastole due to aortic dilatation. The aortic ring and the adjacent intrapericardial portion of the aorta are the first areas of damage during a diffuse aneurysm of the ascending aorta, suggesting that dilatation is a precursor to aortic regurgitation (Brown et al., 1975). Without correct diagnosis of aortic regurgitation, most patients with MFS die due to aortic insufficiency.
MFS patients also suffer from abnormalities of flow-mediated endothelium-dependent vasodilation, an early marker for arteriosclerosis. One study showed that endothelial cell signal transduction may be mediated by the luminal glycocalyx and mechanotransduction may be mediated by the conduction of physical forces through the cell (Wilson et al., 1999). Since a mechanical force must be balanced by an equal and opposite force, it must be mediated by the underlying subendothelial matrix containing microfibrils composed of fibrillin. MFS patients exhibit an abnormality in the composition of fibrillin and when a force is exerted on the microfibrils, it may not adequately perceive the applied force, thereby preventing normal mechanotransduction. The inadequately-composed fibrillin seems to interfere with normal cell attachment and the ability of these cells to resist external forces. Such complications would be the reduction of large-artery distensibility, increased cardiac workload, increased pulse wave velocity, and a decreased ability of the aorta to withstand an increased wall stress (Wison et al., 1999). The decreased ability of the aorta to withstand an increased amount of wall stress may be due to fibrillin complicating the structural integrity of elastin, an integral component of arterial compliance.
Many MFS patients also suffer from pectus excavatum (Pex), a birth defect that results in a depression of the sternum and anterior chest (Lawson et al., 2005). Depending on the severity of the depression of the sternum and anterior chest wall, it could displace the heart and lungs resulting in a decline in cardiorespiratory function, which could either be a low stroke volume or decreased pulmonary function exacerbated by mild to moderate exercise. Many sufferers of Pex report a shortness of breath, chest pain, and overall fatigue. After surgical repair of the sternum and anterior chest wall, many patients reported improved exercise tolerance. A statistical analysis of forced expiratory flow after the corrective surgery showed a 17% increase in older patients as well as those with severe restriction before the surgery, consistent with the report of improved exercise tolerance. The reduction in forced expiratory flow is thought to be caused by an increased airflow resistance in the smaller airways (Lawson et al., 2005). The surgical repair alleviated some of the pressure being placed on the smaller airways, thus reducing some resistance to air flow. Also, the reduction of pressure by a depressed anterior chest wall and sternum increased the venous return to the heart to the right atrium, increasing the stroke volume.
One possible treatment of MFS is ¢-adrenergic-blocking agents. Studies have shown that these agents have the capacity to slow the rate of growth of the aortic root. However, the growth is still abnormal, suggesting that patients with MFS still need surgical correction of the aorta. The ¢-adrenergic-blocking agents work by decreasing the inotropy of the heart, the chronotropy of the heart, thereby decreasing the rate of volume and pressure change in the ascending aorta (Milewicz et al., 2005). ¢-adrenergic-blocking agents must be administered early in the onset of the disease because an increased body weight and end-diastolic aortic diameter of 40 mm or greater reduce the efficacy of these agents. Another possible treatment of MFS is composite valve graft repair in which both the aortic valve and ascending aorta are replaced and the coronary ostia are reimplanted (Milewicz et al., 2005). One study showed that 93.5% percent of MFS patients receiving the graft repair were alive after 5 years, 91% were alive after 10 years, and 59% were alive after 20 years. However, one downside to this graft procedure was the incidence of the dissection of the downstream aorta in 36% of the patients. Even though complications still arise after the surgery, the statistical results show a vast improvement of life expectancy in MFS patients. ¢-blockers should be implemented indefinitely after the surgery to help reduce aortic growth.
Treatment of MFS in children is similar to that of adults but the grafting should wait until the child can fully accept a graft of sufficient size that would allow future growth of the aorta. If the children are less than 5 years old, it is suggested that they keep their mean blood pressure below 80 mm Hg resting and below 110 mm Hg after exercise. Since ¢-blockers could pose significant risks on the development of the aorta, they must be monitored continuously. Pregnant women with MFS should also take b-blockers continuously with echocardiograms occurring frequently before parturition. The stress of labor should be reduced in MFS women via epidural anesthesia (Milewicz et al., 2005). The future treatment of MFS involves preventing the disintegration and dilapidation of the elastic fibers around the aorta and the reduction of TGF-¢ cytokines since there has been a positive correlation between the increase of the cytokines and a deficiency of function in fibrillin-1-containg microfibrils. Inappropriate TGF-¢€ activation and signaling is most heavily seen in the developing lung and other tissues associated with MFS, especially the aortic wall. These cytokines must be heavily regulated and any disturbance of their regulation could lead to MFS.
Although MFS is classified as a connective tissue disorder, it has huge ramifications in both cardiovascular and pulmonary function. The cardiovascular ramifications include an increase in carotid pulse pressure leading to aortic dilation, aortic regurgitation, mitral valve prolapse, increased cardiac workload, and aortic dissection. The pulmonary ramifications are mainly caused by pectus excavatum that result in the displacement of the heart and lungs thereby lowering stroke volume, shortness of breath, chest pain, and overall fatigue. Many of these symptoms can be treated by surgeries such as inverting the sternum or the replacement of the aorta. ¢-blockers can help to reduce the abnormal growth of the aorta until surgery can be performed in MFS patients. The future of treatment of MFS could lie within gene therapy where the mutant gene encoding fibrillin-1 could be replaced with a properly-encoding gene.