Familial Thoracic Aortic Aneurysm and Dissection

Familial thoracic aortic aneurysm and dissection is a heritable disease of the thoracic aorta, usually autosomal dominant, that causes aneurysm, dissection and rupture without the multisystem features of a connective tissue syndrome. It is also called non-syndromic heritable thoracic aortic disease.

About 20% of people with thoracic aortic aneurysm or dissection have an affected first degree relative. A pathogenic variant is found in a minority of families (about 20 to 30%), so a negative genetic test does not exclude familial disease.

Genes include ACTA2 (about 14% of familial cases), MYH11, MYLK, PRKG1, LOX, MAT2A and FOXE3. Syndromic genes (FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, COL3A1) cause overlapping disease and are tested in the same panel.

Penetrance is incomplete and age dependent, and dissection can occur at smaller diameters than in sporadic disease, especially with ACTA2, MYH11 and MYLK variants. Onset is typically in the 30s to 50s, earlier than sporadic disease.

Pathophysiology.

Variants affect the vascular smooth muscle contractile apparatus (ACTA2, MYH11, MYLK, PRKG1) or extracellular matrix and signalling proteins (LOX and TGF-beta signalling genes), so the media loses elastic fibres and smooth muscle and degenerates.

Wall stress rises with diameter (law of Laplace), so the risk of dissection increases sharply over 5 cm, although it can occur earlier in some genotypes.

Genotype specific features include premature coronary disease, early stroke and a Moyamoya like cerebrovascular disease with livedo reticularis and iris flocculi (ACTA2), and patent ductus arteriosus (MYH11). PRKG1 and MYLK variants are linked to dissection with little or no prior dilatation.

Growth rate averages 1 to 2 mm a year. Growth over 3 mm in a year, or over 5 mm in 6 months, is high risk.

Most patients are asymptomatic, with the disease found on screening or incidental imaging. Acute dissection presents with abrupt tearing chest or back pain, syncope, hypotension, pulse deficit, neurological deficit, aortic regurgitation murmur and signs of tamponade or malperfusion. Aortic regurgitation develops with root dilatation. Features of other vascular involvement include coronary events and stroke.

Examination often shows few syndromic features, but joint hypermobility, striae, pectus deformity or arachnodactyly point to syndromic disease.

• Echocardiography: aortic root and ascending aorta diameters with z-scores (body surface area and age), valve morphology (bicuspid valve should be excluded), and regurgitation.
• CT angiography or MR angiography of the entire aorta at diagnosis, and of the arch vessels and brain for ACTA2 variants. MR angiography is preferred in the young to avoid radiation.
• Genetic testing: a panel including ACTA2, MYH11, MYLK, PRKG1, LOX, FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, COL3A1, MAT2A and others, after counselling. Test affected family members first, then offer cascade testing to first degree relatives.
• Family screening: first degree relatives of an affected person should have aortic imaging at diagnosis and every 1 to 2 years, from adolescence (earlier with a young onset family history), unless a family variant is known and the relative does not carry it.
• Assess for hypertension, atherosclerosis and drugs that harm the aorta (stimulants, fluoroquinolones).
• Ghent type clinical scoring, to exclude Marfan syndrome, and examination for vascular Ehlers-Danlos and Loeys-Dietz features.

Differential diagnosis.

• Marfan syndrome, Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome.
• Bicuspid aortic valve aortopathy and sporadic degenerative aneurysm.
• Turner syndrome and Noonan syndrome.
• Aortitis (giant cell arteritis, Takayasu arteritis, syphilitic aortitis), and traumatic or hypertensive dilatation.

Medical therapy (slows growth and lowers wall stress).

• Target blood pressure under 130/80 mmHg (some centres aim for under 120/80) with resting heart rate 60 to 70 beats/min.
• Beta blocker: metoprolol succinate 25 mg orally daily, increased to 200 mg daily (maximum 400 mg daily); monitor heart rate and blood pressure; reduce in severe hepatic impairment; avoid in severe asthma. Alternative: bisoprolol 2.5 to 10 mg daily (reduce in eGFR under 20 mL/min/1.73 m2).
• Losartan 50 mg orally once daily, increased to 100 mg daily (maximum 100 mg), as add on or alternative (potassium and creatinine at 1 to 2 weeks); evidence for slowing growth comes from Marfan syndrome and is extended to related disease. Contraindicated in pregnancy, and avoid in bilateral renal artery stenosis.
• Statin when atherosclerosis is present: atorvastatin 40 to 80 mg daily.
• Avoid fluoroquinolones (risk of aortic aneurysm and dissection), stimulants and decongestants, and heavy isometric exercise (heavy lifting, straining). Moderate aerobic activity is encouraged. Avoid contact and competitive sport when the aorta is dilated.
• Stop smoking, and treat sleep apnoea.

Surgical thresholds (repair before dissection).

• Aortic root or ascending aorta: 5.0 cm or more in most heritable disease, and 4.5 cm or more for high risk genotypes (ACTA2, MYH11, MYLK, PRKG1), a family history of dissection at a smaller size, growth over 3 mm in a year, severe regurgitation, or when other cardiac surgery is planned. In sporadic disease the usual threshold is 5.5 cm.
• Descending thoracic aorta: 5.5 cm or more (5.0 cm in high risk heritable disease), or rapid growth.
• Technique: valve sparing root replacement when the valve is suitable, or composite valve and graft replacement (mechanical valve needs warfarin to INR 2.5 to 3.5; bioprosthesis needs aspirin 75 to 100 mg daily). Endovascular repair of the descending aorta is used selectively because of poor wall quality, and open repair is preferred in younger patients.
• Brain MRI and coronary assessment before elective surgery in ACTA2 disease.

Acute aortic dissection (emergency).

• Immediate intensive care, with arterial line. Analgesia: fentanyl 25 to 50 microgram intravenously, repeated.
• Anti-impulse therapy: esmolol 500 microgram/kg intravenous bolus then 50 microgram/kg/min, increased by 50 microgram/kg/min every 4 minutes to a maximum of 200 microgram/kg/min; or labetalol 20 mg intravenously over 2 minutes, then 40 to 80 mg every 10 minutes to a maximum of 300 mg, or 0.5 to 2 mg/min infusion. Aim for heart rate under 60 beats/min and systolic pressure 100 to 120 mmHg. Add nicardipine 5 mg/h (increase by 2.5 mg/h every 5 to 15 minutes to a maximum of 15 mg/h) after beta blockade. Avoid vasodilators alone.
• Type A dissection: emergency surgery. Type B: medical therapy, with endovascular repair for malperfusion, rupture, refractory pain or hypertension, or rapid expansion.

Counselling. Explain inheritance (50% risk to each child), the risk of dissection with pregnancy, avoidance of triggers, and the need for lifelong imaging. Offer reproductive options (prenatal and preimplantation testing).

Monitoring. Imaging at 6 months after diagnosis, then yearly if stable (every 6 months with rapid growth or near surgical threshold). Whole aorta MR or CT every 2 to 3 years. Blood pressure and heart rate at each visit. Potassium and creatinine at 1 to 2 weeks after starting losartan, then yearly.

Referral and escalation. Refer every confirmed case and every family to an inherited aortic disease service. Urgent referral for chest or back pain, syncope, growth over 3 mm in a year, aortic regurgitation with symptoms, or size at a surgical threshold. Immediate emergency referral for suspected dissection.

Special groups.

• Pregnancy: counsel before conception. Risk of dissection is highest in the third trimester and postpartum. Continue metoprolol, stop losartan, and monitor with echocardiography every 4 to 8 weeks. Vaginal delivery with epidural is acceptable when the root is under 4.0 cm; caesarean delivery is favoured when the root is over 4.5 cm or growing.
• Children and adolescents: start surveillance in carriers; medical therapy with a beta blocker or losartan is used by specialist decision, since evidence is limited.
• Older adults: lower starting doses and attention to orthostatic hypotension; atherosclerotic disease may coexist.
• Region specific: syphilitic and tuberculous aortitis and Takayasu arteritis should be considered in the differential where prevalent.