Promising new treatment for Marfan syndrome
An investigational treatment for Marfan syndrome is as effective as the standard therapy at slowing enlargement of the aorta, the large artery of the heart that delivers blood to the body, new research shows. The findings indicate a second treatment option for Marfan patients, who are at high risk of sudden death from tears in the aorta.
The results were presented at the American Heart Association’s annual meeting in Chicago and appeared online the same day in The New England Journal of Medicine.
“For years, standard medical therapy for Marfan syndrome consisted of giving patients beta blockers, which lower heart rate and blood pressure, reducing stress on the wall of the aorta,” said study co-author Alan C. Braverman, MD, a cardiologist at Washington University School of Medicine in St. Louis. “This new study suggests that we have a second option for patients that appears to be as effective as standard treatment.”
The second option is Losartan, an angiotensin receptor blocker. Past research in mice and smaller clinical trials suggested that this class of drugs might actually be superior to beta blocker treatment for Marfan syndrome. Angiotensin receptor blockers commonly are prescribed to treat high blood pressure.
People with Marfan syndrome have weak connective tissues and tend to develop unusually long arms, legs and fingers. In addition to heart problems, patients often develop problems with the eyes, lungs, bones and joints. Patients with the condition are at high risk of sudden death from a tear in the aorta, also called an aortic dissection.
Though there is no cure for Marfan syndrome, treatment with beta blockers and preventive surgery to replace the section of the aorta adjacent to the heart has increased lifespan to near normal. But physicians have continued to look for more effective therapies, especially since some patients on beta blockers experience side effects such as tirednessand nausea.
So investigators in the Pediatric Heart Network of the National Institutes of Health (NIH), including Braverman and senior author Ronald V. Lacro, MD, a cardiologist at Harvard Medical School and Boston Children’s Hospital, conducted a clinical trial comparing the beta blocker Atenolol with Losartan.
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[tab title=”Conceito” ]Marfan syndrome, also called Marfan’s syndrome is a genetic condition that an individual inherits from a parent who also has the condition, or a parent with a faulty gene in their sperm or egg. The fault is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. The syndrome affects connective tissues – the fibers that help to provide support and structure to other tissue and organs. Marfan syndrome can affect different parts of the human body, including the heart, blood vessels, bones, joints, and eyes. Sometimes, the lungs and skin are also affected..[/tab]
[tab title=”Epidemiologia” ]According to the National Health Service (NHS), UK, about 1 in every 5,000 British people has Marfan syndrome. It affects males and females equally. Although it is mainly an inherited condition, in about 25% of cases no close relative with the same condition is identified. A person with Marfan syndrome has a 50% risk of passing it on to each offspring. Although Marfan syndrome is incurable, there are therapies that can improve the patient’s quality of life. Individuals with Marfan syndrome tend to have long arms, legs and fingers. Often their arm-span is longer than their height. [/tab]
[tab title=”Etiologia” ]A fault (mutation) in the FBN1 gene on chromosome 15 causes Marfan syndrome. Chromosome 15 encodes fibrillin-1, a type of glycoprotein. The Fibrillin 1 protein is vital for the formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is the defining feature of connective tissue in animals. In other words: A defective gene stops the body from producing Fibrillin 1. Fibrillin 1 is a protein. It helps give our connective tissue elasticity and strength. Connective tissue need elasticity so that we can move and flex. Connective tissue needs strength to support organs and various body parts. Most healthy individuals have an abundance of Fibrillin in their eyes, bones and aorta. Individuals with Marfan syndrome have a lack of Fibrillin. So their bones grow longer than normal, and other symptoms and complications develop. An autosomal dominant condition – even if one parent has Marfan syndrome, the child can inherit it. The majority of people with this syndrome inherited it form a parent. Approximately 1 in every 4 patients, though, has no parent with the condition (spontaneous Marfan syndrome). In cases of spontaneous Marfan syndrome something went wrong with the Fibrillin gene (mutation) in the egg or sperm of the parent – the parent did not have the syndrome, but their sperm/egg developed the genetic mutation.[/tab]
[tab title=”Sinais e Sintomas” ]What are the signs and symptoms of Marfan syndrome? A symptom is something the patient feels and reports, while a sign is something other people, such as the doctor detect. For example, pain may be a symptom while a rash may be a sign. As Marfan syndrome can affect varying parts of the body, it has no unique signs and symptoms; however, the following constellation of symptoms are usually sufficient to make a diagnosis: Very long limbs Long fingers/toes Dislocated lenses Aortic root dilation. Experts say there are several possible signs and symptoms that involve the skeleton, eyes and cardiovascular system. Signs and symptoms vary between individuals, from mild and limited to certain body parts, to severe and affecting several body parts. According to the National Health Service (NHS), UK, about 10% of cases have severe symptoms; which tend to worsen with age. Skeleton (bones, teeth) signs and symptoms: Dolichostenomelia – long limbs. Wrists may be thin and weak. Arachnodactyly (achromachia) – very long and slender fingers/toes Pectus carinatum – protruding sternum (breastbone) Pectus excavatum – sternum caves in Extremely flexible joints Long and narrow face Small bottom jaw – can occasionally cause speech disorders Overcrowded teeth Most individuals are slim Flat feet Individuals are generally much taller than average height High palate – this can sometimes cause speech disorders Hammer toes Stooped shoulders Stretch marks on the skin not explained by pregnancy or weight gain Some individuals may experience pain in the joints, bones and muscles.[/tab]
[tab title=”Diagnóstico” ]The doctor will study the patient’s family and medical history. The physician will try to determine whether the patient has had any illnesses or symptoms that may be linked to Marfan syndrome signs. The doctor will also listen to the patient’s heart, check the skin for stretch marks, and observe the length and features of the patient’s arms, legs, fingers and toes. As signs and symptoms can vary enormously between cases, diagnosis may be challenging. Other conditions with overlapping symptoms, such as Ehlers-Danlos syndrome or Beals syndrome need to be ruled out. When diagnosing children the doctor may refrain from a definitive diagnosis and wait till the child is a teenager, when signs and symptoms are more prominent. Ghent Criteria – doctors often us a diagnostic criteria called Ghent Criteria, named after the Belgian city where doctors determined which features to include on the list. While some are easy to spot, others require diagnostic tests, such as: Echocardiogram – to check the state of the heart, valves and the aorta. EKG (electrocardiogram) – to check heart rate and rhythm. Slit lamp eye exam – to check for dislocated lenses. Imaging scans – such as a CT or MRI scan, to check the lower back for signs of dural Ectasia.[/tab]
[tab title=”Tratamento” ]Marfan syndrome is incurable, however, various therapies are available today to alleviate symptoms and minimize or prevent possible complications. The doctor will develop an individualized treatment program, the details of which depend on which body parts and systems are affected. Skeletal system (bones and joints) – the patient needs to be regularly evaluated so that any changes in the spine or sternum (breastbone) are detected, especially when the individual is a child and is still growing. It is important that abnormalities are treated promptly, because sometimes they can undermine the proper functioning of the heart and lungs. If necessary an orthopedic brace, or even surgery may be required. Ocular (eyes) – the patient should have regular eye exams so that any vision problems are detected and treated immediately. According to the National Marfan Foundation, most problems can be corrected with glasses (spectacles) and lenses. Sometimes the patient may have to undergo corrective surgery. Cardiovascular system (blood vessels and the heart) – the patient will also need regular assessments of the aorta and heart function. It is important to detect and treat any problems early, in order to prevent complications. The National Marfan Foundation advises patients with heart problems to wear a medical alert bracelet and to go straight to hospital if any chest, back or abdominal pain is felt. Beta-blockers may be prescribed for heart valve problems. Sometimes surgery is needed to repair the aorta or replace a heart valve. Prompt surgical intervention is an important preventive measure against possible aortic dissection (tear or rupture of the wall of the aorta). CNS (central nervous system) – if the covering of the spinal cord becomes inflamed (dural ectasia) the patient may need medication for symptoms of pain. Physical activity – as patients tend to be tall they may be encouraged to join sports teams. This may be dangerous if the sport involves physical contact. It is important to ask your doctor what sports are suitable for you or your child.[/tab]
The study included 608 patients with Marfan syndrome at 21 medical centers nationwide. Patients were ages 6 months to 25 years and had enlarged aortas. Half of these participants were randomly given Losartan, the investigational treatment, and the other half received Atenolol, the standard therapy, but in higher doses than physicians typically prescribe to see if this would increase the beta blocker’s effectiveness.
After following participants for three years, the investigators reported no differences between the two groups in the growth rate of the aorta. They further observed similar rates of tears in the aorta, similar numbers of surgeries required to repair these tears and no difference in the number of deaths between the two groups.
“This trial demonstrated that Marfan patients treated with either Atenolol or Losartan had very slow rates of aortic growth, and each group tolerated their medications well,” said Braverman, who treats patients at Barnes-Jewish Hospital. “While beta blockers may be the gold standard for this condition, these results suggest we must use effective doses. This is also an important alternative therapy for the smaller number of patients who are intolerant to beta blockers.”
Braverman also pointed out that ongoing research, including clinical trials currently underway, will continue to shed light on the different effects of these drugs. Investigators would like to determine whether factors such as a patient’s genetic makeup, age and severity of disease favor one drug over the other, or a combination of the two.