In the news...
Actor Alan Thicke: Another Prominent Hollywood Figure Known To Have Died of An Acute Aortic Dissection
Hollywood actor, Alan Thicke, died due to an acute aortic dissection. This is the same cause of death that led to the tragic loss of life of fellow Hollywood comedian and actor John Ritter over 13 years ago in Los Angeles. An acute aortic dissection can mimic a heart attack and if not detected and treated emergently, nearly 40% of all incidents of aortic dissection lead to death. Yet, many of the 25,000 people a year who die from an aortic dissection could potentially be diagnosed before the dissection and treated so a dissection is prevented.
What is an Aortic Dissection?
An aortic dissection occurs when there is a tear in the wall of the aorta, the major artery coming out of the heart. The tear allows the blood to ‘dissect’ from inside the lumen of the aorta into the wall. As the dissection progresses, the wall is torn apart and weakened, leading to aortic rupture and sudden death.
Alan Thicke complained of chest pains while playing hockey on December 13th. His chest pains were most likely due to the acute tear in the aorta and the following aortic dissection. His dissected aorta ruptured three hours later, ultimately leading to his death. Alan Thicke’s aortic rupture was caused by his aortic dissection.
How To Prevent an Aortic Dissection?
Much is written about how the flaw in the aorta that leads to dissection is “undetectable” and “untreatable.” However, many people of the 25,000 people a year who die of aortic disease can be diagnosed before the dissection, and treated so that a dissection is prevented. Typically, there is a widening or ballooning out of the aorta, called an aneurysm, before the dissection occurs. These aneurysms progressively grow larger without symptoms. While people can live with a growing aneurysm for years, when a dissection occurs, it often kills quickly within a matter of hours. If the aneurysm is detected, it can be surgically repaired to prevent a dissection.
The aorta is the main vessel that sends blood away from the heart to the rest of the body. It is shaped like a candy cane and is typically about as wide as a garden hose (2.5-3.5 cm). When blood is pumped by the heart, it first travels through the aorta. An aortic aneurysm is a widening, bulging, or ballooning out of a portion of the aorta. Aneurysms usually occur where there is a weak spot in the aortic wall.
What Are the Risk Factors For Aortic Aneurysms and Dissections?
There are several factors that can increase the risk of dissection, including genetic and environmental influences:
Genetic factors can increase the risk for aortic disease. If you have a family member who has had an aortic dissection, this is a red flag that other family members may also be at risk for an aortic dissection. After John Ritter’s death, his family members had imaging to determine if they had an undetected aneurysm. It was found that John’s brother did have an aneurysm. He had it surgically repaired, and is alive and well today. Had he not taken preventative measures, the chances for aortic dissection were considerably high.
Genetic syndromes like Marfan, Loeys-Dietz and vascular Ehlers Danlos syndrome can predispose to aortic dissection.
Environmental factors that increase the chance to develop an aortic aneurysm or dissection include the following:
- Uncontrolled hypertension (high blood pressure)
- Bicuspid aortic valve
- Weight lifting (http://www.iradonline.org/articles/lifestyle_recs.html for recommendations regarding lifestyle and work)
- Trauma to the aorta (e.g. being in a car accident)
To learn more about the different types of genetic risk, review the Ritter Rules.
Contact email@example.com with questions.
The John Ritter Research Program got off to a great start this year. Two months into 2016, the group has already published new research identifying two new genes for aortic disease. Your contributions to support the research program are instrumental in making this rapid pace of research possible. A brief description of these papers follows.
1. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.
Published in: The Journal of Clinical Investigation. 2016 Feb 8. pii: 83778. doi: 10.1172/JCI83778. [Epub ahead of print]
Kuang SQ, Medina-Martinez O, Guo DC, Gong L, Regalado ES, Reynolds CL, Boileau C, Jondeau G, Prakash SK, Kwartler CS, Zhu LY, Peters AM, Duan XY, Bamshad MJ, Shendure J, Nickerson DA, Santos-Cortez RL, Dong X, Leal SM, Majesky MW, Swindell EC, Jamrich M, Milewicz DM.
The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.
2. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.
Published in: Circulation Research. 2016 Jan 12. pii: CIRCRESAHA.115.307130. [Epub ahead of print]
Guo D, Regalado ES, Gong L, Duan X, Santos-Cortez RL, Arnaud P, Ren Z, Cai B, Hostetler EM, Moran R, Liang D, Estrera AL, Safi HJ, Leal SM, Bamshad MJ, Shendure J, Nickerson DA, Jondeau G, Boileau C, Milewicz DM.
RATIONALE: Mutations in several genes have been identified that are responsible for approximately 25% of families with familial thoracic aortic aneurysms and dissections (TAAD). However, the causative gene remains unknown in 75% of families.
OBJECTIVE: To identify the causative mutation in families with autosomal dominant inheritance of TAAD.
METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with TAAD. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was performed to investigate mutations in candidate genes in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg had significantly lower lysyl oxidase activity when compared with the wild type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.
CONCLUSIONS: These data, along with previous studies showing the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
ACTA2 mutations are responsible for disease in approximately 20% of families with thoracic aortic aneurysms and dissections(TAAD). Dr. Milewicz directs the John Ritter Research Program and her research group identified ACTA2 as a gene that causes TAAD in 2009. The Milewicz group has now published an analysis of clinical data collected from a large group of people (close to 300) who have ACTA2 mutations. This information is important in medical management of patients with ACTA2 mutations. The publication can be accessed by clicking on the article “Aortic Disease Presentation and Outcome Associated with ACTA2 Mutations” available here.
Questions? Email us at firstname.lastname@example.org
Your generosity helps us support families with aortic disease, identify new genes and pathways that cause this condition, and develop guidelines to improve the survival of patients. This year your support helped researchers from the John Ritter Research Program publish a total of 21 papers in peer reviewed journals, listed below. Thank you for your support.
1. MFAP5 Loss‐of‐Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections. Am J Hum Genet. 2014 Dec 4;95(6):736‐43.
2. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. J Biomech. 2014 Nov 1. pii: S0021‐9290(14)00552‐1.
3. RNF213 rare variants in an ethnically diverse population with Moyamoya disease. Stroke. 2014 Nov;45(11):3200‐7.
4. Use of genetics for personalized management of heritable thoracic aortic disease: How do we get there? J Thorac Cardiovasc Surg.2014 Aug 5. pii: S0022‐5223(14)01043‐5.
5. A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium). J Am Coll Cardiol. 2014 Aug 26;64(8):832‐9.
6. Aortic dilatation with bicuspid aortic valve. N Engl J Med. 2014 Aug 14;371(7):683.
7. Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon). Circulation. 2014 Jun 24;129(25):2691‐704.
8. Essential Hypertension vs. Secondary Hypertension Among Children. Am J Hypertens. 2015 Jan;28(1):73‐80.
9. Cell biology. Dysfunctional mechanosensing in aneurysms. Science. 2014 May 2;344(6183):477‐9.
10. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF‐β expression and connective tissue features. FASEB J. 2014 Aug;28(8):3313‐24.
11. Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament‐associated proteins in vascular smooth muscle cells. J Biol Chem. 2014 May 16;289(20):14075‐88.
12. Aortic Valve Operative Outcomes in Marfan Patients Study Group. Early and 1‐year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J Thorac Cardiovasc Surg. 2014 Jun;147(6):1758‐66, 1767.e1‐4.
13. Molecular diagnosis in vascular Ehlers‐Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg. 2014 Jul;60(1):160‐9.
14. Vascular Ehlers‐Danlos syndrome: exploring the role of inflammation in arterial disease. Circ Cardiovasc Genet. 2014 Feb;7(1):5‐7.
15. Surgical treatment of bicuspid aortic valve disease: knowledge gaps and research perspectives. J Thorac Cardiovasc Surg. 2014 Jun;147(6):1749‐57, 1757.e1.
16. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J Clin Invest. 2014 Mar 3;124(3):1329‐39.
17. Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms. Atherosclerosis. 2014 Feb;232(2):361‐8.
18. IL‐6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin‐1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome. J Am Heart Assoc. 2014 Jan 21;3(1):e000476.
19. Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A. 2014 Jan;164A(1):106‐12.
20. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med. 2014 Feb;24(2):53‐60.
21. Single‐nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome. Genet Med. 2014 Jan;16(1):53‐9.
Dianna M. Milewicz, MD, PhD and Frank R. Arko III, MD talk about raising awareness for aortic disease and the future of research on this disease. They reiterate the goals of the John Ritter Foundation for Aortic Health and discuss the diagnosis of aortic disease in both non-emergency and emergency settings. Read this insightful article here.
Amy Yasbeck is this year’s recipient of the 2014 Aortic Disease Advocacy Award for her work in establishing the John Ritter Foundation for Aortic Health. The University of Kentucky Aortic Program created the award to honor individuals who have raised awareness of diagnosis, treatment and prevention of aortic diseases. The awardees will be honored at the University of Kentucky 2014 Aortic Symposium Dinner on September 5, 2014.
Thank you to the Omaha World-Herald for this powerful story of how medical education and process change saved a life. Thank you, Nebraska Methodist Health System, our TAD Coalition partner, for your efforts to educate your medical team on aortic dissection! Read the story here.
The John Ritter Foundation (JRF) announced it was selected as an official charity of the TCS New York City Marathon to take place on Sunday, November 2, 2014. What a great opportunity to increase awareness of thoracic aortic disease, as well as raise funds to support education and research!
The JRF is currently recruiting runners to join Team Ritter. For more information or to sponsor the team, please read the announcement on the JRF website.
Congratulations, John Ritter Foundation!!
Tim Ealer’s father, George, passed away due to complications of an aortic dissection. Since then, Tim has learned that this disease can run in families. He spoke with a reporter about his dad and the importance of screening (aortic imaging) if you have a family history of thoracic aortic aneurysm and/or dissection. Watch the interview here: Tim Ealer on 41 Today (NBC/WMGT).
Learn more here: What Is Aortic Disease?
Many people contact the John Ritter Foundation for Aortic Health and the John Ritter Research Program looking for support groups. Unfortunately, very few currently exist. We would like to identify existing groups and facilitate new groups. If you are interested in finding a support group or know of an existing group, please complete this survey which will be available through December 3, 2013: https://docs.google.com/forms/d/1YO3sKI8Lu2V4z49kq-1fh4wfI-7XGAhaoFoM-4JmEWU/viewform