Common blood pressure drug reduces aortic enlargement in Marfan syndrome

marfansyndromeuk1.jpgA common drug that is used to treat high blood pressure in the general population has been found to significantly reduce a dangerous and frequently fatal cardiac problem in patients with Marfan syndrome.

Results of the COMPARE (COzaar in Marfan PAtients Reduces aortic Enlargement) study reveal that patients treated with losartan (Cozaar) had a significantly reduced rate of aortic enlargement after 3 years compared to patients who did not receive the treatment.

“Our study is the first large, prospective randomized study to assess the effects of losartan on aortic enlargement in adults with Marfan syndrome, and confirms previous findings in a mouse model,” said lead investigator Maarten Groenink MD, PhD from the Departments of Cardiology and Radiology at Academic Medical Centre in Amsterdam, The Netherlands.

“We’re very excited to see that such a commonly used drug that is not expensive and has a familiar side-effect profile could have a significant effect on this very serious and frightening risk factor for these patients. These findings may change standard clinical management.”

Marfan syndrome, a heritable connective tissue disorder, affects 2-3 in 10,000 people. It causes progressive enlargement of the aorta, making it prone to rupture, which can be fatal in more than 50% of cases. Currently, the only effective treatment is prophylactic surgical aortic root replacement.

Read More: Yottafire

Dysfunctional TGF-beta signaling contributes to Loeys-Dietz syndrome associated aortic aneurysm

marfan syndrome uk logo squarePatients with the connective tissue disorder Loeys-Dietz syndrome (LDS) are at high risk for aortic aneurysm. LDS results in the presence of missense mutations within either of the genes encoding receptors for TGF-β. LDS-associated mutations are predicted to reduce TGF-β signaling; however, aortic tissue samples from LDS patients indicate that TGF-β signaling may be enhanced.

In this issue of the Journal of Clinical Investigation, Harry Dietz and colleagues at Johns Hopkins School of Medicine developed a mouse model of LDS, in which transgenic animals expressing Tgfbr1 or Tgfbr2 with LDS-associated mutations recapitulated human phenotypes. Using this model, the authors determined that even though the mutated TGF-β receptors were functionally defective, there was evidence of increased TGF-β signaling as indicated by elevated Smad2 phosphorylation. Furthermore, development of aortic aneurysms in these mice was ameliorated by treatment with an Angiotensin II type 1 (AT1) receptor antagonist.

In a companion commentary, Alan Daughtery and colleagues at the University of Kentucky discuss the therapeutic implications of this study on the use of AT1 receptor agonists to treat LDS-associated aneurism.

Source: Journal of Clinical Investigation

Learning to Defuse the Aorta

losartanWhen Dr. Hal Dietz arrived at Johns Hopkins University in the 1980s, he became obsessed with helping children with Marfan syndrome, a rare and often fatal disorder that can cause the aorta, the large blood vessel that carries blood from the heart, to grow and grow until it bursts.

“Nothing we were doing seemed to make a difference in their lives,” he said.

These doomed children had a distinctive look that clearly had a genetic basis. They were typically very tall and thin, with long arms, legs and fingers. They often had unusually flexible joints, flat feet and teeth that were crowded in their mouth.

“I decided to study genetics with the sole incentive to identify the gene for Marfan syndrome and ultimately to understand the mechanism,” said Dr. Dietz, now director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins.

That journey has led to surprising discoveries about Marfan’s causes and a soon-to-be published clinical trial of a drug that may help its sufferers.

Dr. Dietz’s work also inspired research that may lead to a blood test that detects enlarged aortas, potentially saving thousands of lives, even among those who do not have Marfan syndrome.

Read More: The New York Times

Broken limbs, dislocated hips and joint pain: Woman on battling rare, inherited condition

edsKatie, 34, lives in Essex. Eleven years ago she was diagnosed with Ehlers-Danlos syndrome, a condition that causes her regular injuries, even in her sleep. She says:

“By the time I reached my seventh birthday, I had already broken my arm three times. I seemed to be forever falling over and hurting myself and I was always covered in bruises. Everyone just assumed I was clumsy. But, just like my mother and sister, I was hypermobile – or double-jointed as we called it back then – and I used to show off by doing the splits or bending my hand behind my elbow. Being flexible felt like a gift and it was my dream to be a dancer one day.

Then at senior school I began to feel a lot of pain in my joints, especially in my hips and shoulder blades. I had to take paracetamol two or three times a day to deal with the discomfort and I began to get regular injuries. When I was 14 I dislocated my right hip just walking down the garden path. Another time I dislocated my left ankle on the trampoline at school and had to be rushed to hospital.

By the time I reached 16 I had dislocated my hips about 50 times, but my GP thought all the problems were caused by my dance classes.

“You need to stop,” he told me. “Otherwise you’ll be in a wheelchair before you’re 40.”

My parents got me referred to a physiotherapist for a second opinion. She said I could still dance but my hips were so fragile that I should no longer walk up or downstairs. I had to have all my lessons on the ground floor at school, and at night my dad had to carry me up to my bedroom. I knew there was something seriously wrong with me, but I was worried that people would think I was a hypochondriac so I just soldiered on, all the way through school and university too.

Read More: Express