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92 Elefteriades and Rizzo
Table 1 Summary of Available Information on Incidence of Aneurysm Disease
AAA TAA
Prevalence
Prevalence of AAA in individuals Aneurysm disease is 17th most common
65–89 yrs old cause of death overall, 15th most
Overall: 5.5% (4) common in patients over 65 yrs (3)
Men: 5–7% (5,6)
Women: 1.5% (5,7)
Aneurysm disease is 17th most common
cause of death overall, 15th most
common in patients over 65 yrs (3)
Incidence
Incidence of ruptured AAA (rAAA) is Incidence of TAA is 10.4/100,000 patient
10.6
/
100,000 patient-yrs (7) yrs (equally divided between M and F ) (8)
For men (7)
60–69 yrs old, the incidence of —F older than M at diagnosis (75 vs.
rAAA is 46
/
100,000 patient-yrs 63 yrs)
70–79 yrs old, the incidence of
rAAA is 117
/
100.000 patient-yrs
Rate of acute complications
Yearly risk of rupture is about 1% Incidence of AAD is 3.5
/
100,000 (11,12)
for AAA 4.0–5.4 cm (4) Incidence of rTAA is 3.5–5
/
100,000 (10,11)
Thus total incidence of acute thoracic
phenomena is 7
/
100,000 (11)
79% of ruptures of TAA occur in F (8)
Benefit of screening programs (all re: AAA)
Screening for AAA significantly reduces AAA-related mortality in men 65 to 80 yrs old
(OR 0.57). (No significant reduction in all-cause mortality) (4).
Cigarette smoking is the most significant risk factor distinguishing populations at higher
risk for AAA (OR 5.07) (4).
Prevalence of AAA 5.1% in smokers
1.5% in nonsmokers
89% of AAA-related deaths occur in smokers
To prevent one AAA-related death, only 500 smokers need to be screened,
compared to 1783 smokers
Other risk factors for AAA included (4)
Family history (OR 1.94)
CAD (OR 1.52)
Age (OR 1.71
/
7 Yr interval)
Hypercholesterolemia (OR 1.44)
Cerebrovascular disease (OR 1.28)
Protective risk factors were: female gender (OR 0.17), DM (OR 0.52),
black race (OR 0.53).
(Continued )
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Epidemiology: Incidence, Prevalence, and Trends 93
Table 1 Summary of Available Information on Incidence of Aneurysm
Disease (Continued)
Benefit of screening programs (all re: AAA)
Cost per life saved is approximately $10,000 (10).
A single negative ultrasound screening at 65 yrs suffices, as this virtually excludes future
risk of AAA rupture or AAA-related death (4).
Decision-making (all re: AAA) (see chapter 12 for TAA)
HSTAT meta-analysis of surgical intervention criteria for AAA leads to the
following conclusions:
3.0–3.9 cm AAA Very low risk of rupture Periodic surveillance
4.0–5.4 cm AAA Yearly rupture rate ∼1% Surgery or surveillance
5.5 cm or larger AAA Substantial rupture risk Surgery advised
Trends
The incidence of rAAA is increasing The incidence of TAA is increasing
dramatically (7) dramatically (8)
1971–1986: 4.9
/
100,000 patient-Yr Increased three times over 15 yrs
Current: 10.6/100,000 patient-Yr
Abbreviations: AAA, abdominal aortic aneurysm; AAD, acute aortic dissection; CAD, coronary artery
disease; HSTAT, health services
/
technology assessment text; TAA, thoracic aortic aneurysm.
Table 2 Leading Causes of Death
Ages 65+ All ages
Heart disease 563,390 Heart disease 685,089
Cancer 388,911 Cancer 556,902
Stroke 138,134 Stroke 157,689
COPD 109,139 COPD 126,382
Alzheimer’s 62,814 Trauma 106,277
Influenza 57,670 Diabetes 74,219
Diabetes 54,919 Influenza 65,183
Kidney disease 35,254 Alzheimer’s 63,457
Trauma 34,335 Kidney failure 42,453
Septicemia 26,445 Septicemia 34,069
Hypertension 18,657 Suicide 31,484
Parkinson’s 17,566 Liver disease 27,503
Pneumonia 15,850 Hypertension 21,940
Arteriosclerosis 12,336 Parkinson’s 17,997
Aortic aneurysm 12,040 Homicide 17,732
Benign neoplasm 10,838 Pneumonia 17,335
Liver disease 10,210 Aortic aneurysm 14,810
Suicide 5,248 Perinatal 14,378
Anemia 3,539 HIV 13,658
Peptic ulcer 3,110 Benign neoplasm 13,563
Abbreviation: COPD, chronic obstructive pulmonary disease.
Source: From Ref. 3.
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94 Elefteriades and Rizzo
70s, this rate rises to over 100 per 100,000 patient years. (This corresponds to one
out of every thousand men in their 70s suffering rupture of AAA each year.)
The incidence of thoracic aortic aneurysm is also about 10 per 100,000
patient years (8). Women and men have a similar incidence, but the age at diagnosis
is a decade higher in women (70s) than in men (60s).
RATE OF ACUTE COMPLICATIONS OF
CHRONIC AORTIC CONDITIONS
This book is about acute aortic diseases, so we are especially interested in the
rates at which aneurysms, abdominal and thoracic, rupture or dissect.
For patients with abdominal aortic aneurysms about 1% of those with
moderate-sized aneurysms (4.0–5.4 cm) will suffer rupture each year. The rate
rises, of course, for larger aneurysms. For abdominal aortic aneurysms larger than
5.5 cm, the rupture risk exceeds the surgical risk, and pre-emptive surgical extirpa-
tion is recommended (4).
Among patients with thoracic aortic aneurysms, the rate of rupture, dissec-
tion, or death rises to 14.1% per year for aneurysms 6 cm or more in diameter (9).
This is a huge number, representing a virulence beyond that of most other diseases.
The behavior of thoracic aortic aneurysms is covered fully in Chapter 12.
The total yearly incidence of rupture or dissection of thoracic aortic
aneurysm is about 7% per year, equally divided between rupture and dissection
(10,11,12). A curious and as yet unexplained finding is that 79% of thoracic aortic
aneurysm ruptures occur in women (2,11,12).
Benefits of Screening Programs
The epidemiological implications of screening programs have been studied quite
extensively for abdominal aortic aneurysms (but not for thoracic) (4,13).
Screening programs based on abdominal ultrasound clearly detect aneurysms
effectively and reduce the number of aneurysm-related deaths. The medical care
cost per single aneurysm-related death prevented is about $10,000 USD (13).
One very important benefit of screening is that a single negative ultrasound
at age 65 suffices: patients without an aneurysm at this age will simply not die of
aneurysm rupture (4).
Efforts have been expended to define populations at risk whose routine
screening would be more cost-effective than screening the general population.
Family history, age, male sex, coronary artery disease, cerebrovascular disease, and
hypercholesterolemia all represent incremental risk factors for aneurysm disease,
and, thus, constitute potential criteria for opportunistic population screening. However,
one other characteristic dwarfs the statistical significance of those other risk factors:
cigarette smoking (4). AAA is five times more common in smokers, and 89% of all
aneurysm ruptures occur in smokers. So, screening smokers is a cost-effective way
to look for abdominal aortic aneurysm disease. In fact, one need screen only 500
smokers (compared to 1700 nonsmokers) to prevent one aneurysm-related death.
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Epidemiology: Incidence, Prevalence, and Trends 95
TRENDS
There is little doubt that the diagnosis of aortic aneurysm and its acute compli-
cations are being made with greater frequency. The Swedish group found a
doubling in the rate of ruptured AAA over several decades (7). The Mayo group
found a tripling in the diagnosis of thoracic aortic aneurysm over 15 years (8).
This trend toward increased incidence of aneurysm disease over the last
three decades has been confirmed also for the United States as a whole by the
Centers for Disease Control (14), for Scotland (15), for the Netherlands (16), and
for England and Wales (17).
So, the diseases of interest to this book are definitely being diagnosed more
frequently than ever before.
It is unclear how much of this increased incidence is due to several impor-
tant factors:
Improved Diagnosis in This Era of Common Application of
Three-Dimensional Imaging (Computed Tomography Scan,
Magnetic Resonance Imaging, and Echocardiography)
This seems quite likely an important factor in the increased incidence, as so many
of our aneurysm patients have the first diagnosis made on a 3D image done for
entirely unrelated reasons.
The Aging of Our Population
This is certainly an important factor, as aneurysm disease increases with age.
True Increase in Disease Incidence, Independent of Diagnosis
and Population Age
This possibility is intriguing. Best et al. feel that, in addition to improved diagnosis
of existing cases and aging of the population, a “genuine and persistent rise in the
incidence of AAA has probably occurred” (15). They find this increase especially
interesting in terms of its contrast with the general decrease in arteriosclerotic
vascular disease realized through the vigorous preventive efforts of the last several
decades. If we are living in an era of true increase in the incidence of aneurysm
disease, the relevant causes are obscure.
Genetics
There is an important observation regarding the impact of genetic syndromes on
the epidemiology of thoracic aortic aneurysms. This concerns the relative contri-
butions of Marfan’s disease and bicuspid aortic valve disease to the incidence of
aortic aneurysm.
Marfan’s disease is more widely recognized as a cause of aneurysm and
dissection. Nonetheless, Marfan’s disease is relatively uncommon, affecting only
1 in 10,000 live births. A patient with Marfan’s disease has a 40% likelihood over
a lifetime of developing an aortic dissection.
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96 Elefteriades and Rizzo
While a patient with bicuspid aortic valve has only a 5% chance over a life-
time of developing an aortic dissection, this disease is very common—in fact, this
is the most common congenital condition affecting the human heart. Bicuspid
valve disease affects 2% of the overall population. It has been estimated that
bicuspid valve disease accounts for more morbidity and mortality than all other
congenital heart diseases combined (18,19).
In Table 3, we perform the relative calculations, and, it turns out, bicuspid
valve disease accounts for an order of magnitude more aortic dissections than the
better-appreciated Marfan’s disease.
REFERENCES
1. Anagnostopoulos CE. Acute Aortic Dissections. Baltimore: University Park Press,
1975.
2. Sorensen HR, Olsen H. Ruptured and dissecting aneurysms of the aorta. Incidence
and prospects of surgery. Acta Chir Scand 1964; 128:644–650.
3. Centers for Disease Control. National Center for Injury Prevention and Control.
http:
//
webapp.cdc.gov
/
cgi-bin
/
broker.exe. (accessed 9
/
25
/
06).
4. Health Services
/
Technology Assessment Text (HSTAT). Guide to Clinical Preventative
Services, 3rd ed. Evidence Syntheses, formerly Systematic Evidence Reviews.
National Library of Medicine and NCBI. hstat.nlm.nih.gov (accessed 9
/
24
/
06).
5. Scott RA, Wilson NM, Ashton HA, Kay DN. Influence of screening on the incidence
of ruptured abdominal aortic aneurysm: 5-year results of a randomized controlled
study. Br J Surg 1995; 82:1066–1070.
6. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm. Pathogenesis
and implications. Arterioscler Thormb Vasc Biol 2006; Epub ahead of print.
7. Acosta S, Ogren M, Bengtsson H, Bergqvist D, Lindblad B, Zdanowski Z. Increasing
incidence of ruptured abdominal aortic aneurysm: a population-based study. J Vasc
Surg 2006; 44:237–243.
8. Clouse WWE, Hallett JW Jr, Schaff HV, Gayari MM, Ilstrup DM, Melton LJ III.
Improved prognosis of thoracic aortic aneurysms: a population-based study. JAMA
1998; 280:1926–1929.
9. Davies RR, Goldstein LJ, Coady MA, et al. Yearly rupture or dissection rate for
thoracic aortic aneurysms: Simple prediction based on size. Ann Thorac Surg 2002;
23:17–27.
Table 3 Comparison of Epidemiology of Marfan’s Disease and Bicuspid Aortic Valve,
with Special Reference to Number of Cases of Aortic Dissection Brought on by Disease
AAD likelihood AADs caused (as
Incidence (lifetime) % of population)
Marfan’s disease 1/10,000 (0.01%) 40% 0.004%
Bicuspid aortic valve 2/100 (2%) 5% 0.1%
BAV = 25 × MFD
Note: BAV causes 25 times more acute aortic dissections than MFD.
Abbreviations: AAD, acute aortic dissection; BAV, bicuspid aortic valve; MFD, Marfan’s disease.
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Epidemiology: Incidence, Prevalence, and Trends 97
10. Johansson G, Markstrom U, Swedenborg J. Ruptured thoracic aortic aneurysms:
a study of incidence and mortality rates. J Vasc Surg 1995; 21:985–988.
11. Clouse WD, Hallett JW Jr, Schaff HV, et al. Acute aortic dissection: population-based
incidence compared with degenerative aortic aneurysm rupture. Mayo Clin Proc 2004;
79:176–180.
12. Hagan PG, Nienaber CA, Isselbacher EM, et al. The international registry of
acute aortic dissection (IRAD): new insights into an old disease. JAMA 2000;
283(7):897–903.
13. Wanhainen A, Lundkvist J, Bergqvist D, Bjorck M. Cost-effectiveness of screening
women for abdominal aortic aneurysm. J Thorac Cardiovasc Surg 2006; 132:379–385.
14. Gillum RF. Epidemiology of aortic aneurysm in the United States. J Clin Epidemiol
1995; 48:1289–1298.
15. Best VA, Price JF, Fowkes FG. Persistent increase in the incidence of abdominal
aortic aneurysm in Scotland, 1981–2000. Br J Surg 2003; 90:1510–1515.
16. Reitsma JB, Pleumeekers HJ, Hoes AW, et al. Increasing incidence of aneurysms of the
abdominal aorta in The Netherlands. Eur J Vasc Endovasc Surg 1996; 12:446–451.
17. Filipovic M, Goldacre MJ, Roberts SE, et al. Trends in mortality and hospital admission
rates for abdominal aortic aneurysm in England and Qales. Br J Surg 2005;
92(8):968–975.
18. Fedak PM, David TE, Borger M, Verma S, Butany J, Weisel RD. Bicuspid aortic valve
disease: recent insights in pathophysiology and treatment. Expert Rev Cardiovasc
Ther 2005; 3:295–308.
19. Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000; 83:81–85.
20. Elefteriades JA, Geha AS, Cohen LS. House Officer Guide to ICU Care. Philadelphia:
Lippincott, Williams, Wilkins 1994.
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98 Elefteriades and Rizzo
DISCUSSION AND COMMENTARY
Question for the Authors
Do you feel that routine screening for aortic aneurysm will become standard
practice?
We feel that this is happening already and is appropriate. Elderly males with risk
factors for arterial disease are already being commonly screened by their primary
physicians using ultrasound exams for abdominal aortic aneurysm.
The word is getting out that abdominal and thoracic aortic aneurysm are
genetically transmitted, so family members are increasingly being screened.
For the abdomen, an ultrasound exam suffices. For the thorax, we use a transtho-
racic echo for young individuals (< 40) and a transthoracic echo supplemented by
a CT scan or MRI exam for those family members who are older.
Screening of the general population is occurring incidentally by virtue of
the huge number of CT exams being done for other reasons (trauma, pulmonary
symptoms, chronic smoking, etc.) Many, thoracic aortic aneurysms are picked up
in this way.
In terms of a useful clinical vignette, we use the “thumb-palm” sign to screen
for inherited connective tissue disease (Fig. A). The thumb should not be able to
cross beyond the edge of the palm in a normal individual. In connective tissue
disease, the digits are excessive in length, and the ligaments are lax, allowing the
thumb to cross beyond the edge of the palm. This screening test, remarkably, is free.
Figure A A positive “thumb-palm” sign. This young woman has nonMarfan’s familial
thoracic aortic aneurysm. Note the excessive length of the digits and the hypermobility of
the thumb joint, permitting the thumb to extend beyond the edge of the palm. We recom-
mend screening for such patients.
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99
6
Genetic Basis of Thoracic
Aortic Aneurysms
and Dissections
Dianna M. Milewicz, Hariyadarshi Pannu,
Nili Avidan, Dong-chuan Guo,
and Van Tran-Fadulu
Division of Medical Genetics, Department of
Internal Medicine, University of Texas Medical School,
Houston, Texas, U.S.A.
INTRODUCTION
The natural of aneurysms involving the ascending aorta is to progressively enlarge
over time, leading to an ascending aortic dissection in the absence of prophylactic
repair of the diseased segment of the aorta. Therefore, thoracic aortic aneurysms
and ascending aortic dissections are related conditions, termed thoracic aortic
aneurysms and dissections (TAAD) for this chapter. It is well established that
known genetic syndromes predispose to TAAD, such as Marfan syndrome (MFS).
This chapter will review genetic syndromes that are associated with TAAD,
including MFS and Loeys-Dietz aortic syndrome (LDAS).
The majority of patients with TAAD do not have a named genetic syndrome.
Up to 20% of patients referred for surgical repair have a family history of TAAD,
suggesting a significant genetic component to this disease. Families characterized
with multiple affected members have demonstrated that the condition is typically
inherited in an autosomal dominant manner with decreased penetrance and vari-
able expression. This chapter will also review the mapping and identification of
genes causing nonsyndromic, familial forms of TAAD.
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100 Milewicz et al.
KNOWN GENETIC SYNDROMES ASSOCIATED WITH THORACIC
AORTIC ANEURYSMS AND DISSECTIONS ( TABLE 1)
MFS is an inherited connective tissue disorder characterized by cardiovascular,
skeletal, and ocular complications. MFS is inherited in an autosomal dominant
manner; one-quarter of patients do not have a family history and result from new
mutations (1). The predominant cardiovascular complication associated with MFS
is dilatation of the ascending aorta, typically beginning at the sinuses of Valsalva.
Other cardiovascular complications include both ascending and descending aortic
dissections, along with mitral valve prolapse and regurgitation. The specific ocular
manifestation of MFS is lens dislocation, which is present in approximately 60%
of patients. The skeletal features of MFS include dolichostenomelia (long, thin
extremities), arachnodactyly (long, slender, curved fingers, like a spider’s legs),
scoliosis, joint laxity and pectus deformities. The diagnosis of MFS is currently
primarily a clinical diagnosis that is based on Ghent nosology, which requires
two major manifestations and involvement of third system in an index case
(Table 2) (2). The cardiovascular complications, primarily progressive dilation of
the aortic root leading to an ascending aortic dissection, are the major cause of
morbidity and mortality in MFS (3–6).
Aortic dilation observed in MFS patients is caused by defects in a specific
component of the elastic fiber, fibrillin-1. The elastic fiber is biochemically and
histologically composed of a core of elastin protein surrounded by a peripheral
mantle of 10 nm micro fibrils (7). Microfibrils contain several proteins, with the
major and best-characterized components being the fibrillin proteins, termed
fibrillin-1 and fibrillin-2. Two homologous genes encode the fibrillin proteins,
Table 1 Documented Genetic Causes of Thoracic Aortic Aneurysm
Syndrome Abnormal protein Genetic mutation
MFS Fibrillin-1 FBN1 (>600 mutations)
on chromosome 15
(15q15-32)
MFS2 on chromosome 3
(3p24.2-p25)
MFS2 (TGFBR2)
Lowys-Dietz syndrome TGFBR1
TGFBR2
Beals’ syndrome (congenital Fibrillin-2 FBN2
contractural arachnodactyly)
Turner’s syndrome 45, XO
Noonan’s syndrome
Ehlers-Danlos vascular type Type III Collagen COL3A1
Ehlers-Danlos kyphoscoliotic Procollagen lysine POLD 1
form hydroxylase
Abbreviations: FBN, fibrillin; MFS, Marfan’s syndrome; TGFBR, transforming growth factor
β
receptor.
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Genetic Basis of Thoracic Aortic Aneurysms 101
Table 2 Quick Guide to Diagnosis of Marfan’s Disease
Cardiovascular Pulmonary Skin and Family
system Skeletal system Ocular system system integument Dura history/genetics
Major One required: Four required: Ectopia lentis None None Dural Parent, child, or
criteria Dilatation Pectus carinatum ectasia sibling with
of Asc Pectus excavatum Marfan’s
Ao (± AI), (requiring surgery) disease
involving Reduced upper to lower FBN1 mutation
sinuses of segment ratio or
Valsalva I increased arm span
AAD to height ratio
Positive wrist and
thumb signs
Elbow extension
reduced below 170°
Pes planus
Protrusion acetabulae
Minor MVP (± prolapse) Pectus excavatum Flat cornaes Spontaneous Striae None None
criteria Dilatation main (mod) Increased axial pneumothorax Recurrent or
PA (patients Hypermobile joints length of Apical blebs incisional
less than 40 yo) Crowding of teeth or globe hernias
highly arched palate Hypoplastic iris or
ciliary muscles,
causing
decreased meiosis
(Continued)
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