European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants

At initial diagnosis, we recommend 2D-transthoracic echocardiography (2D-TTE) and complete vascular imaging of thorax and abdomen (neck to pelvis) from the age of 18 years. Imaging has to be performed according to established guidelines for each corresponding technique and obtained values have to be corrected for age, BSA and gender. 2D-TTE is the method of choice in the assessment and follow-up of the aortic root and proximal ascending aorta diameters [25, 26]. Measurements are obtained from the parasternal long axis view at end-diastole according to the leading-edge to leading-edge convention. CT and MRI provide information of the entire aorta and peripheral vessels [27]. CT has the best special resolution but low-dose electrocardiographically gated protocols should be used to decrease radiation exposure. MRI has significant advantages in the follow-up of patients with genetic disorders adding functional information to anatomical data without the burden of ionizing radiation. Aortic root measurement is performed by SSFP cine sequence images and the rest of the aorta by 3D-angiogram. Multiplanar reconstruction of the axial source data can create aortic images in a plane perpendicular to the aortic lumen direction (double-oblique or true short-axis images of the aorta) by CT and MRI. There is general consensus that in both imaging techniques the aortic diameter should be measured with the inner-to-inner convention at end-diastole.

With an aneurysm of the ascending aorta we recommend 2D-TTE with a time schedule based on the individual characteristics of the patient (age, sex) and the TAA (diameter, growth, shape). With an aneurysm in another artery or in the distal part of the aorta, imaging is recommended yearly, the technique depending on the location of the aneurysm. If no aneurysm is found, enlargement of the ascending aorta is monitored by yearly 2D-TTE of the aortic root and the ascending aorta only. We recommend complete imaging of the vascular tree from neck to pelvis once every two to 5 years (Fig. 1). In children, we recommend yearly 2D-TTE from the age of diagnosis, although intervals can be extended depending on clinical judgement. With normal diameters on echocardiography, computerised tomography angiography (CTA)/magnetic resonance angiography (MRA) imaging of the thoracoabdominal aorta is recommended at the age of 18 years (Fig. 1). The choice for CTA or MRA depends on local expertise and availability, always aiming to keep radiation exposure as low as possible.

No systematic imaging of the cerebral vessels is recommended since there is at present insufficient data to make recommendations for treatment. In patients with symptoms potentially related to cerebral vasculopathy, we recommend imaging according to local guidance and clinical review by Neurology and/or Neurosurgery services. Imaging of the coronary arteries should be limited to patients with symptoms suggesting ischemic heart disease and in patients scheduled for elective aortic surgery.

Ophthalmological examination for detection of iris flocculi is recommended at diagnosis and in patients with symptoms. In young children, the ophthalmological examination can be postponed until they can more easily comply.

Elective aortic root replacement should be considered in asymptomatic patients with a maximal aortic diameter between 45 and 50 mm. The American Heart Association (AHA) recommends a threshold of 45 mm [28] and there is currently no European Society of Cardiology (ESC) recommendation for this topic. Since no additional data have become available, there is no consensus on the threshold. The indications for preventive surgery should consider risk factors such as rate of aortic growth, aortic valve dysfunction, body surface area, family history of aortic dissection, and hypertension. Women planning a pregnancy should be considered for preventive surgery at aortic diameters ≥45 mm (see pregnancy section). For elective intervention, we recommend valve sparing aortic root replacement according to David reimplantation technique of valve sparing root replacement when feasible and in the absence of surgical contraindications such as leaflet fenestrations or relevant aortic valve regurgitation. External aortic support procedures, offered in a limited number of centres, has no established role in this population.

Elective replacement of the descending thoracic aorta should be performed according to the ESC, AHA and European Society for Thoraco Vascular Surgery (ESTVS) guidelines [28‐30]. Operative decisions are often difficult and therefore the benefits and risks should be a matter of collective discussion of the patient with the vascular surgeons. There is, at present, no consensus on appropriateness or indications for endovascular procedures in ACTA2 aortopathy. The general rule is to avoid endoprostheses in patients with genetic aortopathies [29].

Type B aortic dissections require initial medical management and surgery in case of complications as in patients without ACTA2 mutations [12]. Endovascular therapy should be avoided in the presence of genetic aortopathies [29].

Scientific proof for medical benefit in patients treated with β-blockers is not available. Medications that reduce hemodynamic stress, such as β-blockers, should be considered in ACTA2 patients, with aortic dilatation (aortic diameter at z-score ≥ 2) or hypertension or progression of aortic dilatation (> 0,3 cm/year) and is reasonable to propose in ACTA2 patients without dilatation. The use of other antihypertensive drugs can be discussed with the treating clinician.

Hypertension should be treated according to the ESC hypertension guidelines which state that all hypertensive patients with aortic dilatation, should have their blood pressure controlled ≤130/80 mmHg [31]. Patients with a pathogenic variant in ACTA2 should be managed according to standard strategies for other cardiovascular risk factors, including dyslipidemia [28, 29].

Patients should be advised to avoid smoking and substance abuse as for all patients. Endurance sports can be of great value to control body weight, blood pressure and fitness. In patients with aortic dilatation/aneurysm, we recommend low static, dynamic sports such as swimming, walking, running and cycling, without competitive spirit. The physical activity level, both in children and adults, should be adjusted by the cardiologist based on the evaluation of aortic dimensions and valvular function. However, we recommend the avoidance of sports with abrupt isometric or static manoeuvers or any other activities with significant increase in arterial blood pressure, such as weightlifting, competitive football, basketball, handball, and tennis.

For preconception care we recommend counselling of all carriers by a pregnancy heart team with cardiologist (specialized in preconception care), obstetrician, and clinical geneticist for evaluation of the aortic risk, counselling of the risks for the future mother, father and children, including discussion of invasive prenatal diagnostic testing and pre-implantation genetic diagnostics [32]. Imaging of the entire aorta is recommended prior to pregnancy. Women who have a medical history of aortic dissection should be advised not to become pregnant. Women with aortic root diameters ≥45 mm should be advised to undergo prophylactic aortic root replacement prior to pregnancy. Teratogenic drugs (e.g. angiotensin receptor blockers such as losartan and irbesartan) should be discontinued – β-blockers should be considered throughout pregnancy (preferably metoprolol or labetalol).

Genetic counselling should be systematically offered to all patients carrying (or at risk for carrying) a pathogenic variant in ACTA2. The counselling aims to collect information and clinical reports of family members, and to inform the consultants of the possible genetic origin of their disease. The genetic work-up should include review with a clinical geneticist who will assess for traits that can potentially recur in patients with ACTA2-related vasculopathy as well as other, previously unreported traits. Clinical annotation is fundamental for expanding and collecting observations that may complete the list of the traits of the disease (either markers or abnormalities deserving care).

Each family member that accepts counselling and testing should give his/her informed consent. The counselling process provides the opportunity for informing and discussing current knowledge and data on potential disease-specific risks, and the benefits of genetic testing in order to facilitate autonomous decision-making. Studies of psychological implication of genetic testing for other cardiovascular diseases have shown that the genetic risk is perceived to be manageable {Oliveri, [33] #47}.