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2 Thoracic arteries

2.1 Arteriosclerotic and acquired inflammatory and congenital diseases of the thoracic aorta

Anatomy of the whole aorta: Reinhard Putz

Clinical findings: Friedhelm Beyersdorf and Thomas Zeller

Conservative treatment: Friedhelm Beyersdorf and Thomas Zeller

Endovascular treatment: Friedhelm Beyersdorf

Surgical treatment: Friedhelm Beyersdorf

Fig. 2.1–1 Overview of the whole aorta.

2.1.1 Anatomy of the whole aorta

The body’s main artery, the aorta, is divided into three parts (Fig. 2.1-1): the ascending aorta, the arch of the aorta and the descending aorta. The ascending aorta starts with the slightly dilated aortic bulb at the aortic valve, which with its three semilunar cusps (valvules) prevents backflow of blood during diastole (Fig. 2.1-2). The cusps consist of very firm, taut connective tissue and are covered with endothelium on both surfaces. They are attached to the inner wall of the junction between the left ventricle of the heart and the aorta and have small nodules (lunules) on their free edges. When blood is flowing back toward the heart, the cusps fill up (aortic sinus), pressing the lunules against each other and usually completely blocking backflow. These delicate edges interlock so finely that even slight changes due to various causes can unfortunately lead to insufficiency.

In the area of the aortic bulb, two arteries supplying the heart are typically already given off from the ascending aorta. The right coronary artery arises from the wall of the right sinus of the aortic valve, and the left coronary artery from the left sinus (Fig. 2.1-2).

Fig. 2.1–2 The aortic valve from above, with the origins of the coronary arteries.

Fig. 2.1–3 Origins of the large arteries from the aortic arch (from Lippert and Pabst 1985).

The ascending aorta does not give off any branches along its subsequent course. It passes into the arch of the aorta without a clear boundary. The upper margin of the aortic arch projects onto the manubrium of the sternum. It has an oblique angle and passes dorsally into the descending aorta, lying in the inferior posterior mediastinum. Normally (in 70% of cases), three large vessels arise from the arch of the aorta in a cranial direction, with considerable variation (Fig. 2.1-3). With the exception of branches to the chest, the entire right half of the head and right arm are supplied by the brachiocephalic trunk, which divides after a few centimeters into the right subclavian artery and right common carotid artery.

The left common carotid artery and left subclavian artery are given off separately on the left.

The most frequent variation is a separate origin, as early as at the aortic arch, of the two large arteries on the right side. Not infrequently, the right subclavian artery arises as the last branch from the aortic arch and then courses as the arteria lusoria behind the esophagus to the right side, where it branches further in the normal fashion. (This variant may seem surprising, but it is clearly explained by the development of the branchial arches.)

The subclavian artery leaves the deep cervical region on each side, lying on the first rib behind the scalenus anterior. The common carotid artery courses upward in a common connective-tissue sheath with the internal jugular vein in the carotid triangle.

The thoracic aorta, which is the initial part of the descending aorta, arises from the aortic arch without any clear boundary. It courses initially in a caudal direction in the posterior mediastinum, lying close to the vertebrae on the left, and gradually turns in the lower chest area toward the anterior side of the vertebral column. Apart from a few small branches to the mediastinum, it gives off nine intercostal arteries on each side, as well as a number of unpaired small arteries to the trachea, the bronchi, the esophagus, and the diaphragm. Small branches go off dorsally to the vertebral column and to the back muscles (Fig. 2.1-4).

The abdominal aorta, descending slightly obliquely from the left, lies anterior to the vertebral column together with the inferior vena cava and divides into the common iliac arteries directly in front of the lumbosacral joint. Like the thoracic aorta, just below the diaphragm it gives off the inferior phrenic artery on the right and left and four lumbar arteries to the dorsal body wall. Paired arteries pass to the adrenal glands, kidneys and ovaries or testicles. The latter arteries descend steeply in the direction of the lesser pelvis. The right renal artery usually reaches the kidney along a course posterior to the inferior vena cava (Fig. 2.1-5).

Fig. 2.1–4 Branches of the thoracic aorta.

Three arteries emerge ventrally from the aorta to the unpaired intestines. The celiac trunk already arises in the aortic hiatus and divides into the left gastric artery, the common hepatic artery, and the inferior gastric artery (Fig. 2.1-6). Approximately 1 cm caudal from it, the superior mesenteric artery arises. A further 1 cm caudally, approximately at the level of the lower margin of the second vertebra, the two renal arteries arise-the right renal artery in a ventrolateral direction and the left renal artery dorsolaterally. The inferior mesenteric artery arises at the left ventrolateral side of the aorta approximately at the level of the fourth lumbar vertebra.

Fig. 2.1–5 Branches of the abdominal aorta.

Fig. 2.1–6a, b Variations of the branches of the celiac trunk (adapted from Lippert and Pabst 1985).

The aortic bifurcation normally lies at the level of the fifth lumbar vertebra, but may also be slightly lower. The common iliac artery arises from it on the right and left sides, dividing further on each side after about 4–5 cm into the external and internal iliac arteries. In the area of the bifurcation, the unpaired median sacral artery arises from the posterior surface of the aorta and courses caudally along the anterior surface of the sacrum.

2.1.2 Clinical pictures and epidemiology of arteriosclerotic and acquired diseases of the thoracic aorta

2.1.2.1 Aortic aneurysms

The most frequent diseases of the aorta are aortic aneurysms. These may be limited to an isolated segment of the aorta (ascending aorta, aortic arch, descending aorta) or may affect several segments (ascending aorta and aortic arch; aortic arch and descending aorta; or thoracoabdominal aortic aneurysms). The Crawford classification is now usually used specifically for thoracoabdominal aortic aneurysms (Fig. 2.1-7).

The incidence of thoracic aortic aneurysms is estimated at 5.9 per 100,000 population per year. Among these, the ascending aorta segment is the one most frequently affected (approximately 50%), followed by the descending aorta (approximately 40%). The aortic arch is affected least often, at around 10% (Bickerstaff et al. 1982).

Multisegmental degenerative aortic aneurysms occur in approximately 12.6% of cases (Crawford and Cohen 1982). Some 1% of cases of sudden death are caused by aortic rupture (dissection 62%, aneurysm 37%, pseudoaneurysm 1%). Atherosclerosis is the principal cause of aortic aneurysms (90%).

The normal diameter of the ascending aorta in adults is < 3.5 cm; in the descending aorta, the normal diameter is < 3.0 cm. In asymptomatic patients, surgery (in the ascending aorta) or endoprosthesis implantation (in the thoracic aorta) is indicated at diameters of 5.0 cm or more.

2.1.2.2 Aortic dissection

Aortic dissection is a frequent disease of the thoracic aorta. It is nowadays usually divided into types A and B using the Stanford classification (Fig. 2.1-8). The frequency of aortic dissection is estimated at 10 per 100,000 population per year (Svensson and Crawford 1992). Aortic dissection involves a longitudinal split in the arterial wall, with separation of the intima–media complex from the adventitia. This gives rise to an original “true” lumen, lined with endothelium, and a “false” lumen surrounded by adventitia. It was earlier thought that aortic dissection was based on an aneurysm with additional Erdheim–Gsell cystic medial degeneration. However, an important role is now ascribed to arterial hypertension; 75% of the patients are hypertensive. Additional risk factors include nicotine abuse and hypercholesterolemia. Hereditary diseases such as Marfan syndrome, Ehlers–Danlos syndrome (with an incidence of one in 5000) and annuloaortic ectasia (5–10% of valve replacement operations in patients with aortic valvular regurgitation) are associated with an increased risk of dissection (Erbel et al. 2001). The prevalence is 0.5–3.0 per 100,000 population per year.

Intramural hematoma is an early stage of dissection. This involves hemorrhage into the media on the aortic wall, starting in the vasa vasorum. Dissection develops from this in 15–41% of patients, and rupture in 5–26% (Erbel et al. 2001). There is a high rate of mortality, at 20–80%. Penetrating ulcer, mainly in the descending aorta, can lead to the development of intramural hematoma and dissection, false aneurysm, and perforation.

In the acute stage, there is fluid blood in the dissection fissure, and this coagulates during the subsequent course within hours, or sometimes only after several weeks. The resulting thrombosis in the dissection fissure is the starting point for “spontaneous healing” of the dissection. When there is strong flow through the dissection channel, thrombosis may not take place, and the false lumen becomes endothelialized. The false lumen then often undergoes aneurysmal dilation and may compress the true lumen.

Fig. 2.1–7 The Crawford classification of thoracoabdominal aortic aneurysms. Type I starts distal to the subclavian artery and ends above the renal arteries; type II also starts distal to the subclavian artery and ends below the renal arteries; type III starts in the region of the distal descending aorta (below T6) and extends to underneath the renal arteries; type IV covers most of the abdominal aorta; type V stretches from the distal thoracic aorta to above the renal arteries.

Fig. 2.1–8 The Stanford classification of acute aortic dissection.

The aortic wall destroyed by the dissection may rupture either immediately or during the later course. Rupture occurs most often in the area of the ascending aorta, into the pericardium, leading to cardiac tamponade. However, rupture may also take place into the mediastinum or mediastinal organs (esophagus, trachea), into the pleura, retroperitoneum, or peritoneum. The branches of the aorta may be compromised or occluded, leading to a wide variety of ischemic organ symptoms. In dissection of the ascending aorta, the coronary arteries, carotids and brachial arteries are at risk, while in dissection of the descending aorta the renal arteries, celiac trunk, and pelvic arteries are affected. In dissection of the ascending aorta, the cusps of the aortic valve are often undermined, leading to acute aortic valve regurgitation of varying degrees of severity. The resulting acute volume loading of the left ventricle can cause left ventricular failure and lead to pulmonary edema. Left-sided heart failure is promoted by the perfusion disturbance in the coronary arteries that is often present at the same time if the right coronary or left coronary sinus of the aortic root is involved in the dissection. The prognosis in this condition partly depends on the extent of the dissection. Signs of impending rupture such as pericardial effusion or pleural effusion and widening of the mediastinum, are associated with a mortality rate of more than 50% (Erbel et al. 2001).

2.1.2.3 Aortitis

Other diseases of the aorta include the appearance of inflammatory cells in the media or adventitia. This condition is known as aortitis, and again it can be divided into two major categories:

Infectious aortitis

Aortitis without known infectious pathogens

Infectious diseases of the aorta with confirmed pathogens can be divided into the following types:

Chronic bacterial infections (not necessarily originating in the aorta per se, but often associated with chronic inflammatory changes in the aorta)

Acute primary infections of the aorta (mycotic aneurysms)

Infections of the aorta after prior surgery (usually involving prosthesis materials made of plastic)

In aortitis without known infectious pathogens, there is again a distinction into cases involving mainly:

The aorta (Takayasu disease) or

Other organ systems, with only secondary involvement of the aorta and other arteries (giant cell arteritis, rheumatoid arteritis, Behçet disease) (see also Part C, on vasculitides)

2.1.2.4 Traumatic aortic rupture

Traumatic changes in the aorta include primarily traumatic aortic rupture in typical locations—i.e., distal to the origin of the left subclavian artery.

2.1.2.5 Surgical anatomy

The aorta is divided into various segments. The segment above the aortic valve up to the sinotubular transition is known as the aortic root. The sinotubular transition marks the boundary between the aortic root and the ascending aorta. The ascending aorta extends from the sinotubular transition to the start of the brachiocephalic trunk. The aortic arch extends from a line lying at right angles proximal to the brachiocephalic trunk to a line lying at right angles distal to the origin of the subclavian artery. The descending aorta is the segment from the left subclavian artery to the aortic hiatus in the diaphragm. The abdominal segment of the aorta is the final section, from the aortic hiatus to the aortic bifurcation.

Table 2.1–1 Normal diameter of the aorta in adults (from Svensson and Crawford 1997).

Segment	Transverse diameter (mm)
Ascending aorta	32
Proximal aortic arch	32
Proximal descending aorta	28
Middle descending aorta	27
Distal descending aorta (at the level of the superior mesenteric artery)	26
Proximal infrarenal aorta	19
Distal infrarenal aorta	17
Common iliac artery	9
Common femoral artery	7

Familiarity with the diameter of the healthy aorta plays an important role in correct decision-making regarding which type of operation is best suited to each patient. The diameters are listed in Table 2.1-1.

2.1.3 Clinical findings

The presentation is usually sudden in onset, sometimes in connection with severe physical or psychological stress (with an increase in blood pressure), and less often starting from a state of complete rest. The rupture event is usually associated with dramatic symptoms. The symptoms depend on the location and extent of the dissection, involvement of branching vessels and of the aortic valve, as well as the onset and location of the rupture. The latter can lead to sudden death that is only explained at autopsy. The major symptom is usually extremely severe chest pain radiating to between the shoulder blades.

2.1.4 Differential diagnoses

Common differential diagnoses include costovertebral syndrome (in which pain is position-dependent and can usually be induced by manual provocation), myocardial infarction (in which the pain center is retrosternal), pulmonary embolism (in which pain is respiration-dependent or there is dyspnea or hyperventilation), acute pleuritis (auscultation), and acute pericarditis (auscultation). More rarely, aortic dissection leads to stroke (with cerebral symptoms such as visual disturbances, syncope, coma, pareses, etc.), perfusion disturbances in the extremities, acute abdomen, or renal infarction (differential diagnosis: embolic occlusion).

2.1.5 Diagnosis

A careful clinical examination of the arterial vascular system usually leads to the first signs suggesting suspected aortic dissection. New systolic and diastolic noise phenomena over the aorta and differences in extremity blood pressure and peripheral pulse require further clarification.

Laboratory tests. Routine laboratory test parameters show only nonspecific findings (elevated erythrocyte sedimentation rate and C-reactive protein, leukocytosis, etc.). However, they are important for follow-up purposes, for recognizing hemorrhage and organ dysfunction. A specific marker that has recently come into use is an increase in smooth muscle myosin heavy chain (SMMHC) values. ECG. The ECG can reveal nonspecific findings such as left ventricular hypertrophy, ischemic ST changes, and infarct patterns with coronary involvement (20%) or low voltage in pericardial effusions. X-ray. Chest radiography plays a subordinate role nowadays, but can reveal elongation and/or widening of the ascending aorta and aortic arch, and in some cases also mediastinal widening. A tumor process, atelectasis, or pneumothorax can be excluded in the differential diagnosis.

Transthoracic and transesophageal echocardiography, duplex ultrasonography. Ultrasound diagnosis is the diagnostic method of choice, as it can be carried out at the bedside. Transthoracic and transesophageal echocardiography are complementary procedures. Two-dimensional imaging can detect the detached inner layer, and color Doppler can differentiate entries and reentries and thrombosed and perfused dissection lumina, and allows assessment of concomitant aortic regurgitation. The sensitivity and specificity of transthoracic ultrasound for recognizing a type A dissection are 77– 80% and 93–96%, respectively. Biplanar transesophageal echocardiography (TEE) has a sensitivity and specificity of 99% and 89%, respectively. The distal extent of the dissection and compromise of the aortic side branches when there is infradiaphragmatic extension can be assessed using color duplex ultrasound.

Spiral computed tomography (CT). In addition to displaying the dissection as a double lumen, spiral CT also allows three-dimensional reconstruction, with precise depiction of the longitudinal extent—a prerequisite for planning endoprosthesis treatment. The sensitivity and specificity are both over 95%.

Magnetic resonance imaging (MRI) and magnetic resonance angiography. Like spiral CT, MRI allows three-dimensional reconstruction and identification of intramural hematoma, but it has several limitations in intensive care conditions (including the long examination time). The sensitivity and specificity of the method are both nearly 100%.

Conventional or digital subtraction angiography and coronary angiography. These procedures are now only carried out in exceptional cases and are indicated for assessing coronary heart disease before planned vascular surgery in type B dissections, for example.

2.1.6 Treatment

2.1.6.1 Conservative treatment

Aortic aneurysm

When the diameter of the aneurysm is not large enough for an intervention to be indicated, treatment essentially consists of secondary prophylactic medication, with a low-normal blood pressure level (< 120/85 mmHg) using β-blockers. Administering a statin to reduce inflammation of the vessel wall is generally recommended. Lifting of heavy weights (> 20 kg) is contraindicated.

Aortic dissection

In addition to symptomatic measures such as relieving pain (with morphine) and treating shock (with volume substitution), heart failure, and kidney failure, the classic treatment initially consists of reducing blood pressure, using negatively inotropic agents to reduce wall tension to prevent the dissection from progressing and leading to impending rupture. Sodium nitroprusside is the agent most frequently used for intravenous continuous infusion to achieve a controlled reduction in blood pressure; β-adrenoceptor blockers are used to reduce the speed of pressure increases (intravenous propranolol or esmolol). Blood pressure values should be reduced as much as possible both in the acute situation and during the subsequent course, ideally to 100–120 mmHg, and this usually requires multiple treatments. Even during initial treatment of the patient in the intensive care unit, noninvasive examinations have to be carried out and a cardiovascular surgery team (from the same institution or elsewhere) needs to be alerted. It is essential to ensure an adequate supply of blood, cross-matched if possible.

In type B dissections, the results of surgical treatment in the acute stage are not superior to those with conservative treatment. Most authors therefore recommend that immediate surgery, or alternatively percutaneous endoprosthesis implantation, should only be carried out when there are life-threatening complications such as rupture or ischemic kidney failure (Erbel et al. 2001). As the natural history is much better for type B dissections that are only diagnosed at the chronic stage, these should be treated electively with surgery or endoprosthesis placement, particularly when there are complications. If there are thromboses in the false lumen without substantial constriction of the aortic cross-section or branches, this can be regarded as a favorable course of spontaneous healing.

2.1.6.2 Endovascular and surgical treatment

The treatment options vary depending on which segment of the aorta is affected:

For diseases of the aortic root and ascending aorta, no endoluminal techniques are currently available. Open surgical procedures therefore predominate in this segment of the aorta.

In the area of the aortic arch, it is also mainly open surgical procedures that are used. However, specialized treatment for specific groups of patients is occasionally possible here using endoluminal stenting techniques, in combination with revascularization of the supra-aortic vessels (hybrid procedures).

In the area of the descending aorta, endoluminal treatment for aortic diseases has proved to be superior to open procedures and is now starting to predominate in the treatment of this segment of the aorta.

The thoracoabdominal segment can also be treated with endoluminal stents after debranching of the intestinal arteries in individual cases (hybrid procedure). Despite this, the majority of thoracoabdominal aortic aneurysms are still treated using conventional surgery.

Surgical treatment of the aortic root and ascending aorta in degenerative aneurysms

Supracoronary replacement of the ascending aorta

Supracoronary replacement of the ascending aorta is indicated in patients in whom the aortic root is not affected by disease and the aneurysm is restricted to the ascending aorta. In supracoronary replacement of the ascending aorta, the aorta is completely transected above the coronary arteries and proximal to the aortic clamp in the first step. Attention should be paid here to ensure, firstly, that there is a sufficient margin in the area of the supracoronary segment to allow the anastomosis to be created; and secondly, to ensure also that not too much of the diseased aortic wall remains. After resection of the aorta, both aortic stumps are initially strengthened with a 0.5-cm wide felt strip, which is sutured onto the aortic stump from outside with 4–0 Prolene using mattress sutures. The suture is not initially tied, to ensure that the diameter is not reduced.

The size of the presealed Dacron tube prosthesis is then selected using a folding measuring instrument. The proximal and distal anastomoses are created with 3–0 Prolene using a continuous technique. The proximal anastomosis is done first, and then the distal anastomosis. Air is removed from the prosthesis before blood flow is restored.

Aortic valve replacement and supracoronary replacement of the ascending aorta

Isolated aortic valve replacement in combination with supracoronary replacement of the ascending aorta is always applicable in the presence of significant aortic valve disease with an aneurysm of the ascending aorta, without marked dilation of the root. In this technique, attention should be given to ensuring that a sufficiently long border is left in the supracoronary aortic resection, since otherwise (e.g., when a biological valve is used) problems may arise when creating the proximal anastomosis. Otherwise, both the valve replacement and supracoronary aortic replacement are carried out using the same technique described above.

Replacement of the ascending aorta and aortic root with reconstruction of the aortic valve

In aortic root aneurysms with an intact, delicate aortic valve without structural defects, two surgical techniques are now available making it possible to do without valve replacement (replacement of the aortic root and ascending aorta, combined with reconstruction of the aortic valve). The surgical techniques that can be used in these cases are the David operation and the Yacoub operation.

David operation

There are numerous modifications and variations (David I–V) on the surgical technique first described by Tirone David. The technique preferred by this author is described here.

After administration of cardioplegia, the aortic root is initially dissected. The ascending aorta is then resected and the aortic root is further dissected, with the coronary ostia visible. As a rule of thumb, a 28-mm presealed Dacron tube prosthesis is used in men and a 26-mm presealed Dacron tube prosthesis in women. The size can be checked again using a folding measuring instrument, and it is best to do this at the still-preserved sinotubular junction. The two coronary ostia are then dissected out and the aortic root is dissected until the subannular sutures can be easily stitched. This is followed by stitching of around 12 subannular felt-supported retention sutures using a large needle (3–0 Ethibond, SH needle). Particularly in the area of the conduction system (the commissure between the right coronary sinus and the noncoronary aortic sinus), attention should be given to ensuring that the sutures are placed immediately underneath the aortic valve annulus (caution: atrioventricular block). Using Prolene suture material, the three commissures are then held up and the presealed Dacron tube prosthesis is placed over the aortic root. The subannular sutures are then distributed uniformly along the distal end of the prosthesis, followed by tying of the retention sutures. It is important that these sutures should not be hemostatic, so that here again the sutures should not be tied too tightly.

The next step in the operation involves attaching the three commissures to the prosthesis. This surgical step is extremely important, and the commissures should therefore be anchored anatomically correctly to the prosthesis. Once the commissures have been attached to the prosthesis with the previously stitched Prolene retention sutures, hemostatic suturing onto the prosthesis of the rest of the aortic border of the aortic root is carried out using 4–0 Prolene. This is best done with a 4–0 Prolene suture with a small needle (V7). The seal on the valve is then checked using saline.

In the next surgical step, first the left coronary ostium and then the right coronary ostium are reimplanted onto the prosthesis using the usual technique. In the final step of the operation, attachment of the distal row of sutures on the prosthesis to the distal ascending aorta is completed. After opening the aortic clamp, intraoperative TEE checking must be carried out in all cases to test the results of the aortic valve reconstruction.

Yacoub operation

The principle of reconstruction of the aortic valve and aortic root, as well as replacement of the ascending aorta, in the Yacoub operation also involves resection of the entire aortic root. The Dacron prosthesis is then trimmed in such a way that three new aortic sinuses are cut out of the prosthesis. After dissection of the aortic root, these neosinuses are then sutured directly onto the aortic valve annulus or residual aortic sinus using a continuous suture.

The modified Yacoub operation is a special form of the technique in which only the noncoronary aortic sinus is replaced with a tongue of the Dacron prosthesis. This is often possible when only the noncoronary aortic sinus shows aneurysmal dilation, while the right and left coronary sinuses have a normal caliber. It is then possible to carry out a supracoronary replacement of the ascending aorta in combination with complete replacement of the noncoronary aortic sinus.

Replacement of the ascending aorta, aortic root, and aortic valve

Mechanical valve conduit

In patients with significant structural aortic valve disease and/or dilation of the aortic annulus, or with aneurysm of the aortic root and ascending aorta, implantation of a valve-bearing conduit may be considered. The fundamental technique nowadays consists of excising the coronary ostia and using an end-to-end technique to reimplant them into the prosthesis (the button technique). After resection of the ascending aorta, dissection of the right and left coronary ostia, and excision of the aortic valve, implantation of the aortic conduit starts with the stitching of the valve sutures using an eversion technique with felt blocks. The sutures must be stitched very close together and distributed evenly along the ring. A sufficiently large valve can be implanted in almost all cases, and one should therefore make sure that not too large a conduit is used, as otherwise too much tension on the annulus is produced, and the sutures are then tied. After this, the coronary ostia are reimplanted—first the left ostium and then the right one. Depending on the quality of the wall, small felt rings can be used to support the 5–0 Prolene suture. One of the most important steps in this operation is correct localization of the site for the ostium anastomosis. It is sometimes advantageous to hold back the heart slightly to prevent later buckling of the coronary arteries. The final step in the operation is the distal aortic anastomosis, which is again created over a previously anastomosed felt strip with 3–0 Prolene.

Overall, this surgical technique can be carried out with excellent results. The Cabrol method (Cabrol et al. 1980) is hardly used any more, as direct reimplantation of the coronary ostia is in principle always possible and is associated with much better results than the Cabrol method. The same also applies to the original Bentall method.

Biological valve conduit (xenograft)

Biological valve conduits are now available (e.g., the Medtronic Freestyle®). In this method, swine aortic valve, aortic root, and proximal ascending aorta are used. In principle, the surgical method is comparable with the mechanical valve conduit, but the following points need to be taken into account:

The suture ring in the biological valve conduit is much more fragile and is thinner than the strong ring used in the mechanical conduit.

The resected and ligated coronary ostia in the swine valve conduit do not correspond to the anatomical position of the human coronary arteries. In most cases, only one coronary ostium can therefore be used for the human left coronary ostium. During implantation, rotation needs to be selected in such a way that the coronary ostia can be appropriately reimplanted.

As the ligature provided by the manufacturer on the biological conduit does not hold 100% securely, it needs to be oversewn again with Prolene. In addition, the ascending aorta on the biological conduit is usually too short and has to be extended with a Dacron prosthesis.

In addition, tube prostheses are available from various companies with integrated biological heart valve prostheses (Shelhigh, Carpentier–Edwards conduit with biological heart valve, etc.).

Allograft implantation

Implantation (actually transplantation) of fresh or cryoconserved heart valves and aortas (allografts) can also be used (like biological conduits) for aortic root replacement. One of the major limitations in using allografts is that they are difficult to obtain, however. In addition, the quality of biological valve conduits has improved markedly in recent years, so that allografts are now hardly ever used for aortic root replacement. There may be possible indications for allograft implantation in patients with endocarditis or in young patients. Data for the long-term results vary widely from center to center and depending on the surgical method used (the free-standing root or inclusion techniques). In contrast to aortic allografts, pulmonary allografts in the aortic position are unfavorable and should not be implanted.

Pulmonary autograft (Ross operation)

The principle of the Ross operation involves transferring an endogenous (autologous) pulmonary valve to the aortic position and using an allograft to replace the pulmonary valve. This surgical technique is based on the desire to replace the aortic valve with an endogenous valve (pulmonary valve). The hope is that this “biological” valve will be much more durable than all the other types of biological heart valve, particularly in younger patients. The disadvantage of the method is that it corrects a univalvular condition using a bivalvular heart-valve replacement. Despite this, the long-term results (see below) are excellent, and the rate of repeat surgery on the new aortic valve is extremely low. If repeat surgery is necessary, it is almost always the pulmonary graft that is needed (for details, see the Results section below). With the introduction of valvular prostheses that can be implanted transfemorally or transapically, this type of second valvular replacement will be associated with even lower risk in the future.

Special techniques for ascending aorta replacement in acute Stanford type A dissection

In acute type A dissections, numerous modifications are available in comparison with operations for degenerative aneurysms. These are based on the fact that the dissected aortic wall is extremely fragile in acute type A dissection, and in addition the aim must be to resect the primary tear. Provided that the primary tear is located in the ascending aorta (as is usually the case), replacing the ascending aorta is sufficient (Fig. 2.1-9). In the rare cases in which the tear is located in the aortic arch, the latter also needs to be replaced.

Both the proximal and distal aortic stumps have to be stabilized with a felt strip and biological glue in all cases. In addition, the distal anastomosis has to be created openly in all cases. Today, the subclavian artery is cannulated in most cases so that cerebral perfusion can be carried out during the procedure on the aortic arch, or while creating the open anastomosis in the area of the distal ascending aorta. If aortic arch replacement is necessary, the supra-aortic branches can be excised as a common island in most cases and reimplanted into the prosthesis later. If the dissection is to include the supra-aortic branches as well, aortic arch prostheses are available nowadays with prefabricated separate Dacron prostheses emerging from the prosthesis for the brachiocephalic trunk, the left common carotid artery, and the subclavian artery.

Another special form of aortic arch replacement is the “elephant trunk” technique. This is discussed with aortic arch surgery below.

Fig. 2.1–9a-e Surgical steps in acute aortic dissection.

In acute dissections, particular attention should be given to the aortic root. Using biological glues and felt strips, it is often possible to carry out supracoronary ascending aorta replacement. However, if the dissection already includes the coronary ostia or has completely destroyed the aortic root, a David operation should be considered as well, possibly in combination with bypass treatment for dissected coronary arteries.

Fig. 2.1–10a, b Hemi-arch replacement with isolated valve replacement.

Conventional aortic arch replacement

Hemi-arch replacement

Hemi-arch replacement means replacement of the concave part of the aortic arch using an open anastomosis technique. This often-used procedure not only allows complete replacement of the ascending aorta, but also specialized arch replacement without the need to reimplant the supra-aortic branches. This surgical procedure can be used for both degenerative aneurysms and dissections (Fig. 2.1-10).

Replacement of the complete aortic arch

Replacement of the complete aortic arch is now carried out in combination with antegrade cerebral perfusion (usually via the right subclavian artery) (Fig. 2.1-11). Replacement of the entire aortic arch can be carried out:

By reimplanting the supra-aortic branches as an island into the Dacron prosthesis (Fig. 2.1-11)

With prosthetic replacement of the three supra-aortic branches (Fig. 2.1-12)

Operations in the area of the aortic arch with antegrade cerebral perfusion are carried out with the patient in hypothermia (bladder temperature 22–25°C). During antegrade cerebral perfusion via the right subclavian artery, the brachiocephalic trunk, left carotid artery, and left subclavian artery are either clamped, closed with rubber bands, or blocked with catheters to prevent reverse bleeding from these vessels, resulting in a potential cerebral steal phenomenon, and to improve visibility in the surgical field. In most cases, a presealed Dacron tube prosthesis 24–30 mm in size is used as a substitute aortic arch, and the anastomoses are created with felt reinforcement. In the first step of the operation, the anastomosis to the descending aorta is carried out, and the island of the supra-aortic branches is then reimplanted into the prosthesis. Initially, a felt cuff is anastomosed onto the aortic stump using 4–0 Prolene with a mattress technique, to provide better quality in the aorta for later anastomoses. After exhaustive elimination of air, perfusion of the whole brain and lower half of the body is restored via the brachiocephalic trunk.

The proximal aortic anastomosis is carried out as the last step in the operation, either in a supracoronary position or as an anastomosis between two prostheses.

Protecting the myocardium is particularly important in these very large and often prolonged operations. The authors exclusively use cold antegrade/retrograde blood cardioplegia with terminal warm reperfusion. In addition, the surgical field is flooded with CO₂. The patient is warmed to a bladder temperature of 35°C. Subsequent stepwise warming up to 36–37°C is then carried out later in the intensive care unit with the appropriate warming mats.

Elephant trunk technique

Fig. 2.1–11a-e Replacement of the aortic arch with a distal end-to-end anastomosis and reimplantation of the supra-aortic branches in an island.

Fig. 2.1–12a, b Complete arch replacement with separate prosthetic use of the brachiocephalic trunk, left common carotid artery and left subclavian artery.

Patients with aortic aneurysms extending from the aortic root over the ascending aorta and the entire aortic arch to the descending aorta represent a special problem. To minimize the problems in these large operations, Borst and colleagues (Borst et al. 1983, 1988) developed a two-step surgical technique in which the ascending aorta and aortic arch are initially replaced, with a segment of a distal Dacron graft being introduced into the descending aorta. The method is known as the “elephant trunk” technique. Numerous modifications of the original technique now exist, such as that described by Svensson and Crawford (1997) (Fig. 2.1-13a-r).

Frozen elephant trunk technique

Another method of replacing the aortic arch and descending aorta via a median sternotomy involves a combined endovascular stent graft implantation with conventional aortic arch replacement (a hybrid technique). This technique was first described by Suto and colleagues (1996) and Usui and colleagues (1999). It was later named the “frozen elephant trunk” technique (Karck et al. 2003, 2005, 2008). In this technique, the entire aortic arch is first dissected free and opened. A special stented Dacron prosthesis with a Dacron prosthesis at its cranial end is then introduced via the aortic arch into the descending aorta. After previous measurement of the diameter of both the distal and proximal landing zones in the area of the descending aorta and of the desired length of the stent, the prosthesis can be implanted via the aortic arch under direct vision. The Dacron prosthesis attached to this Dacron-coated stent is then retracted and used to replace the aortic arch.

Replacement of the distal aortic arch

Operations to replace the distal aortic arch are usually carried out from a left lateral thoracotomy in the fourth intercostal space. These procedures are usually conducted using a heart–lung machine or a left heart bypass. Clamping of the aortic arch is usually done between the left common carotid artery and the left subclavian artery. Extreme care is needed here to protect the recurrent nerve and vagus nerve. In many cases, there is marked arteriosclerosis in these aneurysms, so that there is a relatively high risk of cerebral embolization. The surgical sequence does not differ from that in other aneurysm operations, with appropriate dissection of the proximal and distal aortic stump, suturing of the intercostal arteries, and replacement with a presealed Dacron tube prosthesis.

Endoluminal stent implantation into the aortic arch with prior revascularization of the supra-aortic vessels (hybrid operation)

Another form of treatment for aortic arch aneurysms involves a combination of endovascular stent graft implantation and open surgical revascularization of the supra-aortic branches. This hybrid operation is carried out via a median sternotomy. In the first step, an inverted Y Dacron prosthesis is used to revascularize the brachiocephalic trunk and left common carotid artery. The left subclavian artery is then revascularized with another separate prosthesis limb. Once revascularization of the supra-aortic branches has been ensured, a stent graft is advanced under radiographic guidance from the groin up to the distal ascending aorta. This not only eliminates the aortic arch aneurysm but also occludes the supra-aortic branches (the debranching operation).

Initial experience with this hybrid procedure has been positive, but the surgical effort and costs involved should not be underestimated.

Surgical techniques for replacing the descending aorta

Surgical replacement of the descending aorta

In recent years, surgical replacement of the descending aorta has clearly been overshadowed by endoluminal stent implantation. As discussed in the Results section below, the published results with endoluminal stent implantation are clearly superior to those with the surgical method (in terms of neurological complications, bleeding complications, and the overall postoperative course). The topic is therefore only mentioned here for the sake of completeness. A clear indication for surgical replacement of the descending aorta is present in chronic type B dissections with aneurysm formation, in which the intestinal arteries originate in the false lumen. The dissection flap has to be generously resected here to ensure blood flow both into the true lumen and into the false lumen. In these cases, stent implantation is almost impossible and conventional surgery is the treatment of choice.

The patient is intubated with a dual-lumen tube and positioned for a left thoracotomy—i.e., at an angle of 80–90° on the table. Draping must be carried out in such a way that the left inguinal region remains free in order to connect the heart–lung machine or for an atriofemoral bypass (left heart bypass). The thoracotomy is carried out posterolaterally in the fourth intercostal space. The intercostal space selected depends on whether the operation is on the proximal or distal descending aorta. For the proximal descending aorta, the thoracotomy should be as high as possible, while the sixth intercostal space is usually used for the distal descending aorta. Following appropriate dissection of the descending aorta, the aorta is clamped with pressure control either distal to the subclavian artery or between the carotid and subclavian arteries. To prevent reverse bleeding from the intercostal arteries as much as possible, the descending aorta is clamped in the proximal third or in the middle, and the diseased aortic segment is dissected. All bleeding intercostal arteries are immediately sutured with 4–0 Prolene. The actual anastomosis is then carried out with 3–0 Prolene over felt strips (Fig. 2.1-14). Once the anastomosis has been created, the prosthesis is clamped and the sealing of the anastomosis is tested. The descending aorta is now clamped in a relatively healthy section and the rest of the descending aorta is opened. Arteries of Adamkiewicz or other large intercostal arteries are initially blocked with a red Fogarty catheter and then reimplanted into the prosthesis. All other intercostal arteries are also quickly sutured with 4–0 Prolene. The distal anastomosis is then carried out with 3–0 Prolene over felt strips.

With this anastomosis, special caution needs to be exercised relative to the esophagus, bronchus, and recurrent nerve, which must not be injured during this phase.

Endoluminal stent implantation into the descending aorta

Endovascular treatment is nowadays the treatment of choice for aneurysms in the descending aorta (including acute type B dissection). It requires precise measurement of the size of the aneurysm and of the proximal and distal landing zones for the endovascular stent. There are common sizes of up to 46 mm, but in individual cases larger stents can also be produced individually.

Fig. 2.1–13a-r The modified elephant trunk technique (Svensson and Crawford 1997). (a) Median sternotomy, connection to heart-lung machine via separate cannulation of the superior and inferior venae cavae, and cannulation of the right subclavian artery. Hypothermia and isolated antegrade cerebral perfusion. (b) Before the start of isolated cerebral perfusion, a 10-mm graft corresponding to the size of the distal aortic arch is anastomosed end-to-side to the larger Dacron prosthesis. In the next step, the proximal prosthesis is inverted into the distal prosthesis using the anastomosed side arm. (c) After exposure of the aorta, the proximal aorta is completely transected. (d) The distal aorta is also transected. (e) The inverted prosthesis is then placed in the descending aorta. (f) The prosthesis is anastomosed using a continuous Prolene suture in the region of the proximal descending aorta. (g) This anastomosis is usually sutured in an anticlockwise direction. (h) The two sutures are finally tied. (i, j) If there are any bleeding points, they are managed using felt-supported retention sutures. (k) The inverted prosthesis is now pulled out of the descending aorta prosthesis. (l) An opening for the arch vessels is cut into the prosthesis, and the posterior row of sutures is initially created. (m) The anterior row of sutures is then created. (n) 1. The sutures are tied. 2. Antegrade whole-body perfusion is then carried out via the side arm of the prosthesis. Alternatively, perfusion via the subclavian artery can be continued. (o) Completion of the proximal anastomosis after clamping of the distal ascending aorta prosthesis. (p) Several weeks or months after the operation, the patient is readmitted for replacement of the descending aorta (1) or thoracoabdominal aorta (2). (q) After exposure of the descending aorta, the elephant trunk prosthesis is grasped and clamped. (r) The descending aorta or thoracoabdominal aorta is replaced with the usual technique.

Preoperative clarification includes the issue of whether the stent can be securely anchored distal to the origin of the subclavian artery or whether the proximal landing zone will lie between the left common carotid artery and subclavian artery. If it is necessary to cover the subclavian artery, it needs to be clarified preoperatively whether subclavian transposition should be carried out before the procedure in order to prevent later neurological complications (e.g., posterior cerebral infarction and left upper extremity ischemia). For this purpose, an exhaustive neurological examination needs to be carried out preoperatively to determine:

Whether the two vertebral arteries are equally large

Whether the common carotid arteries are open bilaterally

Whether there are any stenoses in the circle of Willis

These data allow one to decide either for or against subclavian transposition (Weigang et al. 2007a).

The actual surgical procedure is preferably conducted in a hybrid operating room. Aortography is first carried out over the inguinal region. The stent, the diameter and length of which have previously been determined, can then be deployed. In most cases, the stent can be released relatively safely either between the carotid artery and subclavian artery or distal to the subclavian artery. Depending on the extent of the aneurysm, one or two additional stents then have to be introduced for lengthening purposes. After all of the stents needed have been implanted, a final aortography is carried out to assess whether there are any endoleaks. If a proximal or distal endoleak is identified, redilation can be carried out or lengthening of the stent may be needed in individual cases (Fig. 2.1-15).

Fig. 2.1–14a-d Conventional replacement of the descending aorta.

Fig. 2.1–15 Endovascular stent implantation into the descending aorta.

Specialized techniques in acute Stanford type B dissections

Endovascular stent implantation is currently the initial treatment of choice for acute type B dissections as well. It is possible in most cases to close the false lumen entrance and allow perfusion into the true lumen. Open surgery is now only rarely indicated for acute type B dissections.

Several prospective and randomized studies on the topic are currently in progress to assess the precise value of endovascular treatment for acute type B dissections.

Treatment for thoracoabdominal aortic aneurysms

Conventional surgical treatment

Conventional surgery for thoracoabdominal aortic aneurysms is one of the most elaborate interventions in cardiovascular surgery. The techniques that are in use today were developed by Crawford (Svensson and Crawford 1997), Svensson and colleagues (1993), DeBakey and colleagues (1956), and Svensson and colleagues (1994). The operation (Fig. 2.1-16) is carried out with neuroprotection (Weigang et al. 2007b) (cerebrospinal fluid drainage, derived motor-evoked potentials and sensory-evoked potentials) and using a heart–lung machine or atriofemoral bypass. The patient is intubated with a dual-lumen tube and positioned on the right side, so that the shoulders are at an angle of 60° and the pelvis is raised by 30°. The access route for the thoracoabdominal aorta has been described in detail elsewhere (Svensson et al. 1997).

In the first step, the aorta is clamped between the left carotid artery and the subclavian artery (Fig. 2.1-16). Following clamping of the aorta, special attention needs to be given to the proximal blood pressure. If it is too high, it can be reduced using the heart–lung machine and withdrawal of blood. To allow clamping of an as-small-as-possible section of the aorta, the descending aorta is optimally clamped proximally. However, clamping options need to be guided by local conditions. After opening the aorta, the intercostal arteries are initially sutured and the proximal anastomosis is first created over felt strips with Prolene. In chronic dissections, the aorta has to be completely transected to ensure that a false lumen is not overlooked. Injuries to the esophagus in this area must be carefully avoided. After completion of the anastomosis, blood flow into the prosthesis is released to ensure reperfusion of the spinal cord via branches of the subclavian artery as quickly as possible. The distal clamp is then moved further distally (to the level of the aortic hiatus), and additional intercostal arteries are ligated or (after blocking with a red Fogarty catheter) larger ones are sutured into the prosthesis. The prosthesis is then clamped again distally as well, so that antegrade perfusion is possible via the reimplanted intercostal arteries. In the next step, reimplantation of the intestinal arteries such as the celiac trunk, superior mesenteric artery, and renal arteries follows. The precise reimplantation technique depends on local conditions and the extent of the aneurysm or dissection. In individual cases, additional grafts (8-mm Dacron prostheses) also have to be placed to revascularize the intestinal arteries. The more distally the clamp is placed, the less the flow via the heart-lung machine will be. After completion of the entire aortic replacement, the clamps are removed and the patient is weaned from the heart-lung machine.

Fig. 2.1–16a-e Thoracoabdominal aortic replacement: conventional surgical technique. For clarity, the illustration does not show the staged clamping of the aorta, but this needs to be taken into account during the surgical procedure. Particular attention needs to be given to avoid “reverse bleeding” from the intercostal arteries (caution: steal phenomenon from spinal perfusion).

Fig. 2.1–17 Thoracoabdominal aortic replacement: hybrid technique with revascularization of the intestinal arteries and endovascular stent implantation.

A very long phase of hemostasis then follows, which has to be conducted with extreme care to prevent postoperative bleeding. Administration of packed platelets, fresh frozen plasma, and application of fibrin glues, if necessary, are recommended.

Endoluminal stent implantation (hybrid procedures)

Another option for treating thoracoabdominal aortic aneurysms involves hybrid procedures—i.e., a combination of revascularization (by debranching) of the intestinal arteries and implantation of endovascular stents, with covering of the origins of the intestinal arteries (debranching) (Fig. 2.1-17).

2.1.7 Clinical results

In general, the results of surgical treatment in the thoracic aorta have markedly improved during the last 10 years-both in terms of the results of conventional surgical treatment and also endovascular stent implantation.

Supracoronary ascending aorta replacement can nowadays be carried out with minimal perioperative risk for degenerative aortic aneurysms. The risk is of course greater in patients with a type A dissection.

Table 2.1–2 Revascularization of the supra-aortic vessels with endovascular stenting of the entire aortic arch (hybrid procedure).

Authors	Year	Mortality
Weigang et al.	2008	4/26 (15.4%)
Szeto et al.	2007	1/8 (12.5%)
Ancona et al.	2007	0/4 (0%)
Melissano et al.	2007	2/14 (14.3%)
Shah et al.	2006	0/5 (0%)
Bergeron et al.	2006	2/15 (13.3%)

Table 2.1–3 The frozen elephant trunk operation (from Karck and Kamiya 2008).

Authors	Year	Mortality	Paraplegia
Baraki et al.	2007	5/39 (12.8%)	0/39 (0%)
Liu et al.	2006	2/60 (3.3%) 1/60	(1.6%)
Uchida et al.	2006	2/35 (5.7%)	0/35 (0%)
Flores et al.	2006	3/25 (12%)	4/25 (16%)

Due to the option of antegrade cerebral perfusion via the right subclavian artery, procedures requiring hemi-arch replacement or open distal anastomosis can also be carried out with very good short-term and long-term results. This is because:

Extremely deep hypothermia is no longer needed for these procedures (24–26°C bladder or rectal temperature nowadays instead of 18°C).

Antegrade perfusion also allows longer operating times on the aortic arch (i.e., over 30 min) without postoperative neurological complications.

However, operations on the aortic arch are still associated with considerable surgical risk. For this reason, not only conventional complete aortic arch replacement (with implantation of the supra-aortic branches as an island or separate prosthesis replacement for the supra-aortic branches), but also aortic arch replacement using a hybrid procedure can be carried out. The results of the hybrid aortic arch procedure are shown in Table 2.1-2.

Reliable data for the frozen elephant trunk operation are also available in the Ross Registry (Sievers et al. 2005). The study shows that the operation offers an excellent survival rate. The overall rate of repeat valvular surgery is very low with autografts, but the frequency of repeat surgery with allografts (in the pulmonary artery position) has been markedly increasing during the medium term among pediatric patients (Bechtel and Sievers 2005).

2.1.8 Prospects

Diseases of the thoracic aorta are likely to increase during the coming years. This is due to the general increase in life expectancy, as well as the fact that patients with arterial hypertension still do not yet have universal access to good treatment. Although tremendous advances have been made during the last 10 years in this field in particular, the short-term and long-term results are likely to improve even further as a result of innovations in surgical treatment in the thoracic aorta, with endovascular stent implantation and also improvements in the conventional surgical technique. Fenestrated and branched endovascular stents are particularly promising for further improvements in the aortic arch and at the thoracoabdominal junction. A new treatment approach, the implantation of, what is known as a Multilayer Aneurysm Repair System (MARS) stent, may in the coming years make it unnecessary to use branched endoprostheses or hybrid procedures with a debranching operation before endoprosthesis implantation. However, this approach involving modulation of the flow inside an aneurysmal sac, thereby inducing thrombosis of the aneurysm and local pressure reduction, will require further validation of its clinical value to be confirmed in the region of the abdominal aorta and thoracoabdominal aorta first, before it can be used to treat cerebral arteries. It is important that patients with these conditions should be referred to the relevant specialist centers in which the whole range of diagnosis and treatment is available, so that the best individual treatment strategy for each patient can be selected.

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2.1.9 Marfan syndrome and aortic diseases determined genetically

Yskert von Kodolitsch, Tilo Kölbel, Sebastian Debus

2.1.9.1 Clinical pictures and epidemiology

Marfan syndrome is an autosomal-dominant hereditary disease of connective tissue that occurs in one per 10,000 of the population. The disease is caused by mutations in the fibrillin-1 gene (FNB1), which is located in chromosome region 15q21.1 and codes for an important microfibril in connective tissue. The changes in the connective tissue caused by this mutation lead to a risk of early death due to rupture or acute dissection of the aorta, particularly in the area of the aortic root. Marfan syndrome is by far the most frequent genetically determined disease of the aorta and is regarded as a model disease for a wide range of genetically determined aortic diseases that continue to be newly identified (von Kodolitsch and Robinson 2007). This section presents the clinical findings, differential diagnoses, diagnosis and treatment of Marfan syndrome and discusses common features and differences in comparison with other genetically determined aortic diseases.

2.1.9.2 Clinical findings

The prognosis and course of Marfan syndrome are mainly determined by the aortic condition. Untreated patients mainly die due to dissection or rupture of the aorta. With comprehensive care in Marfan centers, the mean life expectancy has increased from only 32 years to over 60 years. By avoiding cardiovascular, orthopedic, and ophthalmologic complications, the patients’ life expectancy and probably also their quality of life can be improved as long as their ability to work and maintain independence are preserved (Silverman et al. 1995; von Kodolitsch et al. 2002; Manow et al. 2010).

Marfan syndrome represents a multiple-system disease. Typical symptoms of the syndrome are above all skeletal changes such as gigantism, altered physical proportions with a comparatively short trunk and long lower and upper limbs, scoliosis and pectus carinatum or pectus excavatum (Figs. 2.1-18 and 2.1-19). Ophthalmological manifestations include lens luxation, myopia, amblyopia, strabismus, secondary glaucoma development and retinal detachment, which can lead to severe visual impairment or complete blindness. Involvement of pulmonary structures can lead to the development of emphysema with acute pneumothorax. Another typical manifestation is dural ectasia, which often causes chronic back pain and can lead to complications in peridural anesthesia or spinal surgery; it can also cause characteristic orthostatic headache as a result of rare dural fistula formation. Hernia formation is observed more often in Marfan patients than in the general population (Sheikhzadeh et al. 2011a). Skin changes are usually only seen in the form of clinically “harmless” striae cutis distensae, although these are quite typical in congenital connective-tissue diseases (Fig. 2.1-19 and 2.1–20).

Fig. 2.1–18a-d Typical clinical signs of Marfan syndrome. (a) The Steinberg thumb sign is positive if the entire thumbnail extends beyond the ulnar edge of the hand when the thumb is bent over (De Paepe et al. 1996). (b) The hand joint sign or Murdoch sign is positive if the thumb overlaps the terminal phalange of the fifth finger when grasping the contralateral wrist (De Paepe et al. 1996). (c) A patient with severe skeletal involvement in Marfan syndrome, with marked scoliosis, asymmetric chest and sternal deformity, which had already led to impaired respiration. (d) The simple pes planus shown here can be scored according to the recent Ghent classification; talipes valgus, which is given two points on the scale, is not present here (Loeys et al. 2010).

With the improved prognosis for patients with Marfan syndrome, a number of additional health problems have emerged. These include ventricular cardiac arrhythmia with sudden cardiac death, mitral insufficiency, endocarditis, sleep apnea syndrome and terminal heart failure (von Kodolitsch et al. 2008).

Fig. 2.1–19a, b The frequency of typical Marfan manifestations in 176 consecutively examined patients with confirmed Marfan syndrome, classified by skeletal manifestations (a) and extraskeletal manifestations (b) in the group studied by Sheikhzadeh et al. (2011a).

Fig. 2.1–20a-d Typical imaging findings in Marfan syndrome. (a) The slit-lamp examination shows the left eye in a Marfan patient in whom the lens has dislocated in an upper temporal direction. Dilated zonular fibers of the suspensory ligament of the lens are visible at the lower edge of the lens. (b) The magnetic resonance image (MRI) of the lumbosacral joint in a patient with classic Marfan syndrome shows marked dural ectasia, which in an erect posture is usually particularly clear in the distal region of the dural sac, due to hydrostatc pressure in the cerebrospinal fluid (Sheikhzadeh et al. 2011b; Habermann et al. 2005). (c) The contrast MRI of the entire aorta shows typical Marfan aortic pathology with a clear, pear-shaped distension of the aortic root but a normal-caliber aorta in the arch and descending thoracic and abdominal parts of the vessel. (d) The contrast computed tomogram taken due to acute chest pain shows acute intramural hemorrhage marked by acute bleeding into the middle layer of the aortic wall, seen here in both the ascending and descending aorta and often leading to progression of the classic aortic dissection and development of a false lumen in the aortic wall. When there is intramural hemorrhage with involvement of the ascending aorta, emergency surgery is indicated in the same way as in a classic aortic dissection (Hiratzka et al. 2010; von Kodolitsch et al. 2003).

2.1.9.3 Differential diagnoses

Typical reasons for a suspicion of Marfan syndrome include an aortic aneurysm or aortic dissection in young adults, manifestations of Marfan in a patient’s family, connective-tissue weakness or hyper-mobility in the extremities and Marfan-like skeletal manifestations (Fig. 2.1-21). Interestingly, Marfan syndrome is only actually confirmed in 28% of individuals with skeletal changes, while the confirmation rate in patients with suspicious eye manifestations is 70% and in those with a positive family history it is 44% (Fig. 2.1-21). Overall, the tentative diagnosis is only confirmed in approximately half of patients with suspected Marfan syndrome. Despite this, Marfan-like changes may also be seen in patients in whom the syndrome has been “excluded” (Fig. 2.1-22). It is extremely important to be unsatisfied with a diagnosis of “Marfan syndrome excluded” in these patients and to conduct a search for other differential diagnoses. Figure 2.1-22 shows the alternative syndromes which are diagnosed and their relative frequency. These syndromes are described below.

Other FBN1-associated diseases

The range of diseases that can be caused by mutations in the area of the FBN1 gene is very wide, ranging from neonatal Marfan syndrome, with an average life expectancy of less than 1 year, to a Marfan-like appearance that is not associated with aortic disease or with any reduction in life expectancy. Only a few forms of isolated thoracic aneurysms and dissections (i.e., with no other extra-aortic manifestations) are associated with FBN1. The mitral valve, aorta, skin and skeletal features (MASS) phenotype is a mild form of manifestation of Marfan syndrome. Mitral valve prolapse syndrome is associated with Marfan-like skeletal manifestations, but mutations in the FBN1 gene and aortic disease have not yet been reported with it. Particularly in pediatric groups of patients, Shprintzen–Goldberg syndrome and Weill–Marchesani syndrome are diagnosed in association with FNB1 gene mutations. Aortic phenotype: the MASS phenotype should not show any progression in the dilation of the aortic bulb, while in neonatal Marfan syndrome aortic dissections are already noted at the intrauterine stage.

Loeys–Dietz syndrome (LDS)

Loeys and Dietz have described a Marfan-like syndrome caused by mutations in the TGFBR1/2 genes, showing aortic disease with syndromal changes that differ clearly from Marfan syndrome in both the aortic and extra-aortic findings (Fig. 2.1-23). Type 1 Loeys – Dietz syndrome is characterized by cardiovascular, craniofacial, neurocognitive and skeletal manifestations (Mizuguchi et al. 2004). The cardinal craniofacial symptoms consist of hypertelorism, cleft palate, cleft or wide uvula, blue sclera and craniosynostosis. Rare manifestations include atrial septal defect, patent ductus arteriosus, type 1 Arnold–Chiari malformation, hydrocephalus, developmental retardation and club foot (Loeys et al. 2005). Type 2 Loeys–Dietz syndrome was first described in 2006 in patients with mutations in the TGFBR1 and TGFBR2 genes who met the clinical criteria for vascular Ehlers–Danlos syndrome, but without having the changes in type III collagen typical of that syndrome. Type 2 Loeys–Dietz syndrome is characterized by the development of arterial aneurysms, hypermobility and at least two additional symptoms that are typical for vascular Ehlers–Danlos syndrome such as intestinal rupture in the viscera, uterine rupture particularly during pregnancy, translucent, silky, brittle, or hyperelastic skin, and atrophic cicatricial tissue. Aortic phenotype: although more than 80% of the affected patients develop aneurysms in the proximal aorta in type 1 and 2 Loeys– Dietz syndrome, there are also often aneurysms in the distal aorta, in side branches of the aorta, in the cervical arteries or head—in contrast to Marfan syndromes. An additional feature of Loeys–Dietz syndrome is pathological elongation and tortuosity in the arteries. Furthermore, the age of manifestation of Loeys–Dietz syndromes is lower, acute vascular complications are located in multiple vascular regions and the risk of rupture and dissection does not depend on the diameter of the aorta.

Aneurysm–osteoarthritis syndrome (AOS)

The clinical presentation of this aortic syndrome is similar to that of Loeys–Dietz syndrome, and it is caused by mutations in the SMAD3 gene. There are mild signs of craniofacial dysmorphia bifid uvula, skeletal changes resembling those in Marfan syndrome, dural ectasia, involvement of the inner organs and skin changes (van de Laar et al. 2011). Osteoarthritides are typical in this syndrome and are not observed in the other aortic syndromes. In addition to vascular complications, mitral valve diseases, pulmonary valve stenoses, septal defects, and patent ductus arteriosus may occur. Aortic phenotype: aneurysms and dissection mainly occur in the aortic root, but can also develop in all of the other vascular segments of the aorta and extra-aortic arteries. The arteries also often have a severely tortuous course.

Fig. 2.1–21a, b Analysis of reasons for the referral of 300 consecutive adults in Hamburg for diagnostic clarification in cases of suspected Marfan syndrome. The methods with which these data were obtained are described in Sheikhzadeh et al. (2011a). (a) The reasons why the referring physicians raised a suspicion of Marfan syndrome. (b) The relative frequency with which the diagnosis was actually confirmed in patients with a specific reason for suspected Marfan syndrome. It is notable that “signs of connective-tissue weakness or joint hypermobility” and patients with “typical Marfan skeletal manifestations” were rarely in fact found to have Marfan syndrome.

Vascular Ehlers–Danlos syndrome (VEDS)

The Ehlers–Danlos syndromes are diseases of connective tissue that are characterized by increased elasticity in the skin, hypermobility in the joints and involvement of internal organs (Beighton et al. 1998). The vascular form of Ehlers–Danlos syndrome is caused by mutations in the type 3 collagen gene (COL3A1). Aortic phenotype: aortic complications occur starting from the mid-20s onward and often affect the aortic arch, descending aorta and abdominal aorta. Dissections and ruptures of the medium-sized arteries often occur. Aortic ruptures during pregnancy and intraoperative complications during vascular procedures are also frequent.

Bicuspid aortic valve disease (BAVD)

Isolated bicuspid aortic valve disease is a relatively frequent cause of aortic dissection (Homme et al. 2006). Aortic dissection associated with the bicuspid aortic valve usually affects relatively young patients with no other cardiovascular risk factors. Bicuspid aortic valve disease is one of the most frequent forms of cardiovascular malformation, with a prevalence of around 1–2%. There is an increased risk of aortic stenosis and aortic insufficiency, infectious endocarditis and aortic dissection. NOTCH1 mutations are only identified as the cause of the disease in a small proportion of the families affected. Aortic phenotype: in contrast to Marfan syndrome, a bicuspid aortic valve with stenosis leads to dilation of the ascending aorta above the sinotubular junction. In cases of insufficiency, Marfan-like dilation of the aortic root may occur, and in rare cases aneurysm formation is possible even without stenosis or insufficiency in the aortic valve (Aydin et al. 2011a). Aortic changes distal to the proximal aorta are typical, particularly when there is a simultaneous aortic isthmus stenosis. Aneurysms can also form after successful replacement of the aortic valve or aortic coarctation repair (Aydin et al. 2011b, 2002; Cotrufo and Della Corte 2009).

Fig. 2.1–22a, b Typical manifestations of Marfan syndrome per person according to the Ghent-1 classification (De Paepe et al. 1996). As discussed in detail by Sheikzadeh et al. (2011a), 300 adults with suspected Marfan syndrome were examined. (a) It was found that a considerable proportion of the patients in whom Marfan syndrome was excluded had a large number of typical Marfan manifestations. (b) The range of final diagnoses in these 300 adults.

Fig. 2.1–23a-c Typical findings in Loeys-Dietz syndrome that should raise doubts regarding a diagnosis of “Marfan syndrome.” (a) Contrast magnetic resonance angiography shows a typical Loeys-Dietz aorta. Although the pear-shaped distension of the aortic root is indistinguishable from aortic pathology in Marfan patients, a patient ductus arteriosus is also visible here, which is atypical in Marfan syndrome. In addition, the abdominal aorta has been replaced with a tubular prosthesis from the renal arteries downward. The development of aneurysms in the abdominal aorta is atypical in Marfan patients. (b) The CT angiography in a patient with confirmed Loeys-Dietz syndrome shows noticeable elongation and contortion in the cerebral vessels. (c) The discretely bifid uvula shown here was noticed during the clinical examination and raised a suspicion of Loeys-Dietz syndrome, which was confirmed by evidence of a mutation in the TGFBR2 gene.

Extremely rare hereditary thoracic aortic aneurysms and dissections (TAADs)

There is no established definition of what TAADs should include. We would use it to cover all of the very rare (prevalence in the general population ≥ 1 per 100,000) monogenic aortic diseases that occur with or without syndromally defined extra-aortic manifestations (von Kodolitsch et al. 2010; Milewicz et al. 2008). The syndromal aortic diseases include dermatochalasis (cutis laxa), caused by mutations in the FBLN4 gene; arterial tortuosity syndrome, caused by mutations in the GLUT10 gene and TAAD with patent ductus arteriosus, caused by mutations in the MYH11 gene. TAAD due to mutations in the ACTA2 gene is associated with marked livedo reticularis and early occurrence of coronary heart disease. Aortic phenotype: depending on the gene involved, this may vary widely. In TAAD associated with ACTA2 gene mutations, dissections occur in both the proximal and distal aorta, but the overall aortic prognosis is similar to that in Marfan syndrome.

2.1.9.4 Diagnosis

Diagnosis of Marfan syndrome

A revised version of the classification, intended to allow easier diagnosis, has been available since 2010 (Table 2.1-4) (Sheikhzadeh et al. 2011a; Loeys et al. 2010). In patients who do not have a confirmed family history of Marfan syndrome, the syndrome is diagnosed if there is evidence of aortic dilation with ectopia lentis or with a causative FBN1 mutation, or with a systemic score ≥ 7 points (Loeys et al. 2010). Evidence of ectopia lentis with an FBN1 mutation known to be the cause of aortic disease is not sufficient to confirm a diagnosis of Marfan syndrome. If there is a family history including confirmed Marfan syndrome, the diagnosis of Marfan is confirmed if there is evidence of aortic dilation or a systemic score ≥ 7 points or ectopia lentis. The systemic score and criteria for a causative FBN1 mutation are specified in the revised Ghent classification (Loeys et al. 2010). Marfan syndrome should not be diagnosed without excluding the clinical signs of alternative diagnoses. The revised Ghent classification provides a list of the criteria (Table 1.2-5).

Diagnosis of alternative aortic syndromes

From our point of view, three diagnostic rules need to be observed. Since Marfan syndrome is by far the most frequent cause of genetically determined aortic syndromes and many of its extra-aortic manifestations also occur in other aortic syndromes, the first rule is, when there is a suspicion of a genetically caused aortic disease, that one must always evaluate whether the clinical criteria for Marfan syndrome are present. If extra-aortic signs of Marfan syndrome are present in addition to thoracic aortic disease, sequencing of the FBN1 gene should be carried out primarily. If the evaluation shows typical manifestations of alternative aortic syndromes, then—particularly if they are typical of Loeys–Dietz syndrome—sequencing of the TGFBR1/2 genes or SMAD3 gene should be carried out first, or other alternatives should be considered if there are relevant clinical signs (see Table 2.1-5 and Fig. 2.1-24). The introduction of next-generation sequencing technology is likely to lead to the establishment of a sequencing strategy that allows diagnosis of all the typical genes responsible for aortic diseases (Baetens et al. 2011).

Another diagnostic rule is that a specific aortic syndrome should not be diagnosed, even if there is evidence of a gene sequence change in one of the potentially causative genes, unless the relevant phenotypic criteria are met. This has been firmly established for Marfan syndrome for a long time and is regulated by internationally recognized classifications (Loeys et al. 2010; De Paepe et al. 1996). The current Ghent classification also defines diagnostic criteria for MASS syndrome, ectopia lentis syndrome and mitral valve prolapse syndrome (Loeys et al. 2010). By contrast, vascular Ehlers–Danlos syndrome is diagnosed using the criteria set out in the revised Villefranche classification (Beighton et al. 1998). The diagnostic signs of Loeys–Dietz syndrome are listed in the new Ghent classification (Table 2.1-5) (Loeys et al. 2010), while the presence of aneurysm–osteoarthritis syndrome has to be tested using the phenotypical abnormalities described in the original publication (van de Laar et al. 2011).

Table 2.1–4 Diagnosis of Marfan syndrome according to the criteria of the revised Ghent classification (Loeys et al. 2010).

A diagnosis of Marfan syndrome is made with the following findings:
A No confirmed family history of Marfan syndrome:
1. Aortic root dilation (Z≥2) or aortic dissection and lens luxation1
2. Aortic root dilation (Z≥2) or aortic dissection and FBN1 mutation
3. Aortic root dilation (Z≥2) or aortic dissection and systemic involvement (≥7 points)1
4. Lens luxation and FBN1 mutation previously noted in an individual with aortic dilation
B At least one relative meeting one of the four criteria above independently of the individual being examined (positive family history):
5. Positive family history and lens luxation
6. Positive family history and systemic involvement (≥7 points)1
7. Positive family history and aortic root dilation (Z≥2 > 20 years, Z≥3≤20 years)1
C Systemic score2:
Systemic characteristic:	Score points:
Positive wrist and thumb sign	3
Positive wrist or thumb sign	1
Pectus carinatum	2
Pectus excavatum or chest asymmetry	1
Talipes valgus	2
Pes planus	1
Pneumothorax	2
Dural ectasia	2
Otto disease (protrusio acetabuli)	2
Reduced leg-body ratio and arm length-height ratio > 1.05 (with exclusion of high-grade scoliosis)3	1
Scoliosis or thoracolumbar kyphosis4	1
Reduced elbow extension (170° or less)	1
Facial characteristics (at least three of the five signs)5	1
Striae cutis distensae	1
Myopia > 3 diopter	1
Mitral valve prolapse	1

1 Requires exclusion of relevant differential-diagnostic clinical signs of Shprintzen–Goldberg syndrome, Loeys–Dietz syndrome, or vascular Ehlers–Danlos syndrome and after TGFBR1/2 mutation analysis, collagen biochemistry examination and COL3A1 analysis if indicated (see Table 2.1-5).

2 Systemic involvement is present at ≥ 7 points (maximum 20).

3 The leg–body ratio, measured from the upper edge of the pubis, is considered abnormal from < 1 at an age of 0–5 years, < 0.95 at age 6–7, < 0.9 at age 8–9, and < 0.85 at age ≥ 10 in whites and < 0.78 in blacks.

4 Scoliosis is present with a Cobb angle ≥ 20° or a height difference between the right and left dorsal halves of the chest ≥ 1.5 cm when the patient is leaning forward.

5 Signs of facial dysmorphia are dolichocephalism, enophthalmos, laterally sloping eyelid axes, malar hypoplasia and retrognathism. Z = Aortic root Z score.

In our experience, there are many patients in whom it is not possible to diagnose a syndrome despite clear evidence of a genetically determined aortic disease. There are also patients who have nucleotide sequence changes in the “aortic genes” who do not have any manifestion of aortic disease. Substantial diagnostic difficulties may arise in children in particular, as many extra-aortic and cardiovascular changes have age-dependent manifestations. In addition, there are no established criteria for recording many signs of dysmorphia and assessing aortic changes, therefore clinical experience is vital. Due to multiple-organ involvement in many syndromes, collaboration between several medical disciplines is always essential. A third diagnostic rule should be that diagnostic assessment of patients with genetically determined aortic diseases should take place in specialized centers (von Kodolitsch et al. 2002). These centers are approved in Germany as part of “outpatient hospital treatment” (Book V, Para. 116b of the German Social Code) (Bekanntmachungen 2007). This regulation permits specialized hospitals to carry out comprehensive diagnosis, including gene sequencing, while approximately covering costs (Manow et al. 2010).

Table 2.1–5 Clinical signs relevant to the differential diagnosis in the revised Ghent classification (Loeys et al. 2010).

Differential diagnosis	Gene	Clinical signs
Loeys–Dietz syndrome (LDS)	TGFBR1/2	Cleft palate/bifid uvula, arterial tortuosity, hypertelorism, diffuse aortic and arterial aneurysms, craniosynostosis, talipes equinovarus, unstable cervical vertebrae, silky and brittle skin, bleeding tendency
Shprintzen–Goldberg syndrome (SGS)	FBN1 and others	Craniosynostosis, mental retardation
Congenital contractural arachnodactyly (CCA)	FBN2	Wrinkled ears, contractures
Weill–Marchesani syndrome (WMS)	FBN1, ADAMTS10	Microspherophakia, brachydactyly, stiff joints
Ectopia lentis syndrome (ELS)	FBN1, LTBP2, ADAMTSL4	Exclusion of aortic dilation
Homocystinuria	CBS	Thromboses, mental retardation
Familial thoracic aortic aneurysm (FTAA)syndrome	TGFBR1/2, ACTA2	Exclusion of marfanoid skeletal manifestations, livedo reticularis, iris flocculi
FTAA with bicuspid aortic valve (BAV)
FTAA with patent ductus arteriosus (PDA)	MYH11
Arterial tortuosity syndrome (ATS)	SLC2A10	Generalized arterial tortuosity, arterial stenoses, facial dysmorphia
Ehlers–Danlos syndromes (vascular, valvular, kyphoscoliotic types)	COL3A1, COL1A2, PLOD1	Aneurysms in the medium-sized arteries, severe cardiac valvular regurgitation, translucent skin, atrophic scars, facial characteristics

Fig. 2.1–24 Diagram of the differential diagnosis in patients with thoracic aortic aneurysms and dissections (TAADs) with a suspected genetic background. The involvement of a specific gene regarded as being causative of TAADs in principle makes it possible to develop specific phenotypes, which are shown in the diagram under each gene. The arrangement of the various syndromes runs from left to right according to declining phenotypic similarity with Marfan syndrome, and on the right shows the TAADs that typically occur without any extravascular manifestations (von Kodolitsch and Robinson 2007). Abbreviations are explained in the text.

2.1.9.5 Treatment

Conservative treatment

The principles used in the medical management of Marfan syndrome have hardly changed during the last 25 years (Pyeritz and McKusick 1979). From the internal-medicine and cardiology point of view, there are five important measures (von Kodolitsch et al. 2008): 1, detailed consultation with the patient regarding lifestyle adjustments and planning for ways of living with moderate impairment of physical activities; 2, administering prophylactic antibiotic treatment against endocarditis; 3, serial cardiological examinations including tomographic assessment of the aorta and if appropriate serial ophthalmological and orthopedic check-ups; 4, prescribing a β-blocker for protection of the aorta; and 5, prophylactic replacement of the aortic root in accordance with the current criteria (Table 2.1-6).

Adults with Marfan syndrome should avoid emotional stress and dynamic exercise such as that involved in running, tennis or volleyball with preference for static exercise such as weightlifting, water-skiing or gymnastics, as dynamic exercise can lead to moderate blood-pressure increases. Contact sport and activities that lead to too-rapid acceleration or abrupt deceleration of movement sequences such as soccer, martial arts, or basketball should be avoided, as should scuba diving with oxygen apparatus or amateur flying in planes that lack pressurized cabins. However, diving with a snorkel and flying in pressurized commercial aircraft are possible without any problems. With regard to competitive sports, participation in billiards, cricket, curling, golf, bowling and sports shooting is possible. With children, the focus is on setting life goals for adulthood that take into account the impaired health resulting from Marfan syndrome, while strict bans on sports are not generally required (von Kodolitsch et al. 2008; von Kodolitsch and Rybczynski 2006). Detailed and individualized counseling for patients with Marfan syndrome is particularly important. In our view, this should include not only detailed discussions but also mention of published self-help guides for patients (Marfan Hilfe [Deutschland] e.V. 2007); information about the support provided by Marfan Hilfe Deutschland e.V. (see http://www.marfan.de/) has also proved helpful.

According to the current guidelines, endocarditis prophylaxis should only be considered if patients have already developed endocarditis or have received an artificial cardiac valve or have valvulopathy after heart transplantation (Wilson et al. 2007). Among 1000 patients with Marfan syndrome, 15 will develop mitral valve endocarditis up to the age of 35 and 84 will develop it by the age of 60 (Rybczynski 2010). The risk of endocarditis in Marfan patients is thus much higher than in patients with idiopathic mitral valve prolapse, for example (Avierinos et al. 2002). In the opinion of experts, endocarditis prophylaxis is therefore also indicated, in addition to the information given in the official guidelines, if the native cardiac valve shows signs of any dysfunction, frequently in the form of aortic or mitral valve insufficiency (von Kodolitsch et al. 2008).

Table 2.1–6 Classic principles of medical management in patients with Marfan syndrome (von Kodolitsch and Robinson 2007).

General measures in adults with Marfan syndrome

Moderate restriction of physical activity

Endocarditis prophylaxis*

Echocardiography and MR angiography of the aorta at annual intervals

β-blockers to protect the aorta

Measures during family planning and pregnancy

Providing information about the 50% risk of inheritance of Marfan syndrome by children

High-risk pregnancy in patients with aortic root diameter > 40 mm or status post heart surgery and cases of severe heart disease

When pregnancy is planned in women with an aortic root diameter≥40 mm, prophylactic replacement of the aortic root should be carried out

Serial (e.g., 3-monthly) echocardiographic check-ups for up to 3 months after delivery

Indication for prophylactic replacement of the aortic root in adults (≥one criterion)

Aortic root diameter ≥ 45 mm

Aortic ratio ≥ 1.5 (normal size, i.e., 20–37 mm divided by actual measurement, corrected by age, gender and body surface area)

Ratio for diameter of aortic root and descending aorta ≥ 2

Increase in diameter of aortic root ≥ 5 mm/year

Indication for prophylactic replacement of the aortic root in children

The operation should be delayed if possible until completion of growth

Assessment of the aortic root diameter is based on the criteria for adults

Aortic root diameters above the upper confidence intervals move further upward during the course of echocardiographic check-ups

Indication for mitral valve surgery

The indication is established in accordance with the current AHA recommendations

* In addition to the indications given in the current AHA guideline recommendations, the view of experts is that endocarditis prophylaxis should be carried out in all Marfan patients in whom any relevant dysfunction of the natural cardiac valve has been diagnosed (von Kodolitsch et al. 2008).

Drug treatment for protection of the aorta previously consisted exclusively of β-blocker administration. The effectiveness of this has been confirmed in a prospective and randomized study which demonstrated a slowing in the rate of aortic root dilation in pediatric patients (Shores et al. 1994). However, animal experiments have shown that angiotensin II receptor blockers such as losartan and matrix metalloproteinase inhibitors also have stabilizing effects on the metabolism of the aortic wall (Habashi et al. 2006). A large study in the United States is therefore currently testing whether the protective effect of losartan on the aorta is superior to the effects of β-blockers in patients with Marfan syndrome.

Pregnancy

There is thought to be a high risk of aortic complications during pregnancy in Marfan patients. According to the current guidelines, the risk of aortic rupture or aortic dissection during pregnancy must be regarded as high if the diameter of the aortic root is ≥ 40 mm or an aortic dissection has already occurred beforehand (Hiratzka et al. 2010). Several authors have reported an increased risk only from 45 mm upwards (Meijbook et al. 2005). Women at increased risk who wish to have children should be advised against pregnancy, or prophylactic aortic root replacement should be discussed with them.

Surgical treatment

The improved life expectancy in patients with Marfan syndrome is mainly achieved by prophylactic replacement of the aortic root, which prevents spontaneous rupture or dissection of the aortic root. The standard operation on a typical aorta with Marfan changes until recently consisted of complete replacement of the aortic root with a valve-bearing conduit (Gott et al. 1999a). The Bentall technique or several of its variants were used in this procedure (von Kodolitsch et al. 1998).

There are two important trends in aortic root surgery for Marfan patients. Firstly, the criteria for prophylactic replacement of the aortic root have become increasingly generous during the last 25 years and the current criterion is a diameter ≥ 45 mm. Continuing improvements in the results, with very low mortality rates in elective operations, have played a role in this, along with a recognition that even slightly dilated aortae with a diameter of 40–45 mm involve a risk of acute complications, while the postoperative course in patients who have survived an aortic dissection is in principle associated with higher complication rates and a poorer quality of life (von Kodolitsch et al. 2008; Gott et al. 1999b).

Secondly, the view is currently becoming accepted that the conduit operation with complete replacement of the aortic root must not be regarded as the standard operation; instead, the primary aim should be to achieve a valve-preserving reconstruction of the aortic root. This changed approach has also been reflected in the current guidelines (Hiratzka et al. 2010). Valve-preserving surgical techniques are derived from Yacoub, along with a modified technique by David. They both developed techniques for reconstructing the aortic root by preserving the physiological valvular apparatus while still keeping a radical resection of the entire proximal aorta. Yacoub’s remodeling techniques have not become established, due to unfavorable long-term results with higher rates of aortic valve insufficiency and therefore reimplantation techniques must currently be regarded as the standard (Fig. 2.1-25). Reconstruction of the aortic root can be carried out with good early and medium-term results, avoiding the disadvantages of valvular replacement with the associated increased risk of thromboembolism and endocarditis (Bernhardt et al. 2011a). The aim in mitral valve surgery is currently to use a valve-preserving approach, and although present experience with mitral valve reconstruction in Marfan patients is not based on a large number of cases, it is highly promising (Gillinov et al. 1994; Bernhardt et al. 2011b).

Fig. 2.1–25 In the current variants of the David operation, the aortic tissue is completely excised along the crown-shaped upper annulus of the aortic sinus. The tissue from the aortic sinus, with the valve-bearing tissue, is preserved. However, this approach removes the aortic tissue from the coronary orifices, and reimplantation of the coronaries into the tubular prosthesis that replaces the aorta is therefore an integral component of all David operations. The illustration shows different variants of the David operation, dividing into David I–V types, proposed by Miller (2003). The upper row in the illustration shows the variants of the operation that are described as David reimplantation techniques. The basic principle in these techniques involves suturing the natural valve-bearing sinus into the aortic prosthesis and attaching the aortic prosthesis both to the base of the sinus and along the upper crown-shaped annulus. The David I operation consists of this basic technique. In the David IV and V operations, the ascending aorta is replaced with an additional, narrower tubular prosthesis and the aortic sinus is formed by a wider tubular prosthesis into what is known as a neo-sinus. The lower row in the illustration shows the variants of the operation that are known as David remodeling techniques. The basic variant in this technique is the David II operation, in which as in the Yacoub procedure the upper, crown-shaped annulus of the aortic sinus is directly sutured to a correspondingly trimmed tubular prosthesis. David uses this surgical method only in patients with no dilation of the lower annulus. In the David III variant, the lower annulus is also stabilized externally with a felt strip that is sutured in.

Treatment for other genetically determined aortic diseases

The principles of medical management of genetically determined aortic diseases, excluding Marfan syndrome, are based on the management of Marfan syndrome. However, there are signs that the practical approach used may be starting to diverge from that used in management of Marfan syndrome, depending on the underlying syndrome and the gene mutation causing the condition. These differences mainly affect the indication for surgical intervention, which sometimes used to be very substantial. It will also be conceivable in the future for specific aortic diseases to be treated with drugs in different ways, depending on the pathological mechanism involved (von Kodolitsch et al. 2010; Milewicz et al. 2008). Table 2.1-7 sums up the surgical treatment recommendations that are taylored to a relevant gene defect or the presence of a specific aortic syndrome (Table 2.1-6).

Endovascular therapy in genetically determined aortic diseases

Endovascular treatment has become established for nongenetic diseases of the descending aorta and infrarenal aorta, due to the lower rates of perioperative morbidity and mortality in comparison with open surgery (Svensson et al. 2008). However, this basically requires the presence of an undilated, healthy vascular segment in which the radial force of the stent graft can achieve a seal. This prerequisite for safe anchoring of the stent graft is certainly present in Marfan syndrome and other hereditary diseases of the aorta if the end of the stent graft is positioned in a vascular segment that has already been replaced during open surgery. Which segments of the aorta are affected varies so widely with the numerous genetic diseases described above that it is hardly possible to make any general statements regarding the possibility of endovascular treatment. However, implantation of rigid stent grafts, particularly proximal bare stents into the aortic arch should be viewed critically in all patients with genetically determined diseases, since excessive pressures at the stent tips can occur in a highly pulsatile vascular segment and can lead to vascular erosion, dilation and rupture.

The use of stent grafts for endovascular treatment of aneurysmal or dissected aortic segments has not yet been sufficiently investigated in these patients. Only case reports and case series with small numbers of patients have been published, which in summary describe the technical feasibility of the procedure with a low rate of periprocedural mortality, but without any long-term results (Baril et al. 2006; Botta et al. 2009; Geisbusch et al. 2008; Nordon et al. 2009). The published results are also inconsistent with regard to the success of the treatment (Botta et al. 2009). A common feature in the published case series is the high proportion of patients who have undergone previous surgery with replacement of the ascending aorta or aortic arch, presence of distal dissection with dilation of the false lumen and a high rate of secondary interventions (Fig. 2.1-26). With the increasing life expectancy and frequent previous operations in patients with Marfan syndrome, for example, the endovascular treatment options in principle represent an attractive and less invasive alternative.

2.1.9.6 Prospects

The increasingly wide range of different drug-based, surgical and interventional treatment options available is likely to lead to growing differentiation in the criteria for using them. Highly individualized decision-making criteria will apply. Molecular genetics will play a progressively important role here (von Kodolitsch et al. 2010). In addition, with the normalization of life expectancy for the affected patients, the issue of quality of life for young patients will also become paramount. The affected patients want to be able to live with as much freedom from prohibited behaviors as possible and to take part in all aspects of occupational and social life, sports and leisure activities. This area will require further research on care provision and the development of programs for rehabilitating patients with Marfan syndrome and other hereditary aortic diseases.

Fig. 2.1–26 Computed tomography of the aorta in a patient with classic Marfan syndrome, showing the prosthesis in the ascending aorta after treatment with a bio-conduit for an aortic root aneurysm with high-grade aortic valve insufficiency when the patient was aged 71. Due to a progressive false-lumen aneurysm with a chronic Stanford type B aortic dissection, with an overall diameter of the aorta of 71 mm, repeat treatment was carried out when the patient was aged 74, with placement of an aortic stent graft following initial stent graft implantation in the aortic arch and descending aorta when the patient was 69. The current CT shows good results with the stent treatment, with successful exclusion of the aneurysm. However, renewed aneurysm formation can be seen at the distal end of the stent graft.

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2.1.10 Adults with congenital aortic isthmus stenosis

Marcus Rebel, Ali Dodge-Khatami, Ali Aydin, Yskert von Kodolitsch

2.1.10.1 Clinical pictures and epidemiology

Congenital aortic isthmus stenosis is also known as aortic coarctation and is a classic clinical picture in pediatric medicine. In most cases, adults with congenital aortic isthmus stenosis have undergone surgical correction while they were children. However, adults with corrected aortic isthmus stenosis have a number of medical problems and a first diagnosis of aortic isthmus stenosis is often only made in adults. This section aims to describe the specific vascular-medicine problems that arise in adults with corrected aortic isthmus stenosis or with a late first diagnosis of the condition. This approach is in accordance with current efforts to treat the situation faced by adults with congenital cardiac defects as a separate medical challenge (Schmaltz et al. 2008).

Aortic isthmus stenosis is defined as a congenital narrowing of the aorta in the area of the distal aortic arch, up to the start of the thoracic aorta at the level of the origin of the left subclavian artery and orifice of the ductus arteriosus; the isthmus is a physiological narrowing of the aorta in this area. The ductus arteriosus is the fetal “diversion” of the pulmonary circulation and links the pulmonary trunk with the aorta; within a few days to weeks of birth, it closes physiologically and regresses to a connective-tissue structure, the ligamentum arteriosum.

With an incidence of 0.2–0.6 per 1000 live births, aortic isthmus stenosis represents 5–8% of all congenital cardiac defects (Brickner et al. 2000; Krieger and Stout 2010). Boys are affected approximately twice as often as girls. The location of the aortic isthmus stenosis is postductal in 75% of cases, while 25% are in preductal locations. The classification of aortic isthmus stenosis into pediatric and adult anatomic forms is now no longer used, as the two types of anatomy occur without any strict age-dependence. Aortic isthmus stenosis is often associated with other congenital malformations; bicuspid aortic valve, patent ductus arteriosus, and cardiac septal defects are the most frequent (Table 2.1-8).

No familial predisposition is present in many patients with aortic isthmus stenosis. In familial cases, there is usually multifactorial inheritance, and autosomal-dominant inheritance is reported more rarely. A family has been described in which aortic isthmus stenoses were inherited over four generations, probably with an autosomal-dominant mode of inheritance, and a high degree of gene penetrance with variable phenotype expression was observed (Beekman and Robinow 1985). Aortic isthmus stenoses often occur in the context of complex syndromes, with Turner syndrome being the one most frequently associated with aortic isthmus stenosis (Table 2.1-9).

There are two hypotheses regarding the cause of aortic isthmus stenosis. In the hemodynamic hypothesis, it is assumed that aortic isthmus stenosis develops on a localized shelf on the posterior wall of the aorta opposite the orifice of the ductus arteriosus. When the ductus arteriosus closes, an obstruction gradually develops in the area of the duct’s orifice (“juxtaductal”), leading to increased resistance (Rudolph et al. 1972). This theory above all explains isthmus stenoses in defects involving left ventricular obstruction such as bicuspid aortic valve, mitral stenosis and subaortic stenosis. However, it does not explain all forms of aortic isthmus stenosis, and in particular does not account for isolated aortic isthmus stenosis with no intracardiac malformations. By contrast, Skoda considered as long ago as 1855 that scattered ductal tissue was responsible for the development of aortic isthmus stenosis. This hypothesis has in the meantime been confirmed by histological analyses (Fig. 2.1-27) (Ho and Anderson 1979). More recent discussion has focused on defective development of cells of the neural crest as the cause of isthmus stenosis (Kappetein et al. 1991).

Table 2.1–8 Malformation associated with congenital aortic isthmus stenosis.

Malformation	Frequency in aortic isthmus stenosis (%) (Kappetein et al. 1991; Becker et al. 1970; Beekman et al. 1981;Campbell et al. 1980; Clarkson et al. 1983; Hesslein et al. 1981; Lerberg et al. 1982; Liberthson et al.1979; Pennington et al. 1979; Pinzon et al. 1991)
Bicuspid aortic valve	15–65
Aortic valve stenosis or regurgitation	2–9
Patent ductus arteriosus (PDA)	10–45
Ventricular septal defect (VSD)	7–47
Hypoplastic aortic arch*	22–63
Atrial septal defect (ASD)	1–18
Mitral valve anomaly (parachute)	4
Intracranial aneurysms	~10

* The aortic arch is defined as hypoplastic relative to the diameter of the ascending aorta:

Proximal arch of the brachiocephalic trunk to the left carotid artery: < 60%

Distal arch of the left carotid artery to the left subclavian artery: < 50%

Aortic isthmus from the left subclavian artery to the insertion of the duct: < 40% of the diameter of the ascending aorta (Moulaert et al. 1976)

Table 2.1–9 Syndromes associated with a risk of congenital aortic isthmus stenosis.

Turner syndrome

Noonan syndrome

DiGeorge syndrome

Loeys–Dietz syndrome

Williams–Beuren syndrome

Down syndrome

Rubella syndrome

Trisomy 18

McCune–Albright syndrome

Klippel–Feil syndrome

Camptomelic syndrome

Shone syndrome

Goldenhar syndrome

Scimitar syndrome

Pierre Robin syndrome

Roberts syndrome

Type 1 neurofibromatosis

Kabuki syndrome

Alagille syndrome

Fig. 2.1–27 In the hemodynamic hypothesis, it is assumed that aortic isthmus stenosis develops on a localized shelf on the posterior wall of the aorta opposite the orifice of the ductus arteriosus. By contrast, Skoda believed that scattered ductal tissue was responsible for the development of aortic isthmus stenosis.

2.1.10.2 Differential diagnosis of aortic isthmus syndrome

Pseudocoarctation refers to elongation and folding of the aorta in the thoracic segment, particularly of the aortic arch and proximal descending thoracic aorta, with no significant pressure gradients. However, there may be an indication for surgery if adjacent organs such as the esophagus are displaced or compressed, or if aneurysmal dilation of the aorta occurs.

Abdominal coarctation, also known as “mid-aortic syndrome” (MAS), is locally circumscribed in two-thirds of the cases. In one-third, however, it may also involve extensive changes. These are usually caused by inflammatory changes such as those seen in Takayasu arteritis or granulomatous vasculitis. The condition is also observed in patients with fibromuscular dysplasia, neurofibromatosis, retroperitoneal fibrosis, extensive atherosclerosis and congenital malformation (Connolly et al. 2002). Typical findings are renal artery stenosis with severe arterial hypertension, while stenoses of the celiac trunk or mesenteric arteries occur less frequently.

2.1.10.3 Clinical findings and course

Children: Two clinical groups are distinguished. Firstly, those with preductal aortic isthmus stenosis, which manifests in the first week of life. In this form of isthmus stenosis, the perfusion of the lower half of the body is dependent on the ductus arteriosus. When the duct closes, acute hypoperfusion of the lower half of the body results. Due to a lack of collateral circulation, afterload increases with acute cardiac and renal failure that require urgent correction of the aortic isthmus stenosis in severely affected neonates. An infusion of prostaglandin E₁ can reopen the ductus arteriosus to stabilize the neonate clinically until emergency surgery can be carried out.

The second group of children with aortic isthmus stenosis remain asymptomatic for a longer period. These children become conspicuous due to hypertension in the upper half of the body and hypotension in the lower half. Typical times for first diagnosis in these children are pediatric check-ups and pre-school medical examinations. At the physical examination, the inguinal pulse may be only weakly palpable, if at all, in comparison with the pulse in the radial artery, depending on the severity of the stenosis. Symptoms include headache, epistaxis and intermittent claudication.

Untreated adults: Untreated adults usually become symptomatic due to their untreated hypertension. Typical symptoms with late diagnosis are headache, epistaxis, intermittent claudication, heart failure and acute aortic dissection. The annual mortality rate in untreated patients with aortic isthmus stenosis is age-dependent and shows a peak frequency in the first year of life. According to data from the first half of the twentieth century, the mean life expectancy for individuals with untreated aortic isthmus stenosis is 34 (Abbott 1928; Campbell and Baylis 1956). Reasons for the high mortality rate include frequent accompanying anomalies with severe cardiac insufficiency (Table 2.1-10). Another extremely important factor is the risk of rupture or dissection of the aorta, which must be regarded as high in the presence of a simultaneous bicuspid aortic valve and due to systemic weakness in the wall of the aorta, particularly in patients with untreated or inadequately controlled hypertension.

Table 2.1–10 Causes of death in patients with untreated aortic isthmus stenosis (Campbell 1979).

Cause of death	%	Average age(years)	Decade of life
Decompensated cardiac failure	26	39	3rd–5th
Rupture or dissection of the aorta	21	25	2nd–3rd
Bacterial endocarditis	18	29	1st–5th
Intracranial bleeding	12	29	2nd–3rd
Aortic isthmus stenosis not the cause of death	24	47	4th–6th

2.1.10.4 Diagnosis

Clinical examination

Blood pressure and pulse: A classic sign of aortic isthmus stenosis both in adults and children is a difference in systolic pressure between the upper and lower extremities. In contrast to the systolic pressure, diastolic blood pressure often shows no differences between the upper and lower extremities (Brickner et al. 2000). Blood pressure is usually the same in the right and left arm, corresponding to a location of the aortic isthmus stenosis distal to the original of the left subclavian artery. When the subclavian artery arises distal to the isthmus stenosis, blood pressure in the left arm may be lower than in the right. Very rarely, when both subclavian arteries arise distal to the isthmus stenosis, it is possible for similarly reduced blood pressures to be present in all four extremities. The current guidelines for diagnostic clarification of hypertension therefore recommend that pulse and blood pressure should be examined and compared in the upper and lower extremities (Warnes et al. 2008). Auscultation: In addition to cardiac murmurs in associated malformations, a typical finding in aortic isthmus stenosis is a short midsystolic murmur that can also be heard for longer than the second heart sound and is best heard in a left paravertebral position. In addition, continuous flow murmurs may be heard over collateral vessels.

Electrocardiography: In children with aortic isthmus stenosis, there are often signs of right ventricular hypertrophy, while signs of left ventricular hypertrophy are typical in adults.

Exercise tests: Ergometric exercise with electrocardiographic or echocardiographic monitoring may be useful, particularly for recognizing exercise hypertension or diagnosing a raised transisthmic gradient (Warnes et al. 2008). However, these examinations are not recommended as a general routine for follow-up in patients with aortic isthmus stenosis.

Imaging

The entire diagnostic work-up for an aortic isthmus stenosis can be carried out noninvasively. For diagnosis and follow-up in patients with aortic isthmus stenosis, the classic chest x-ray has been abandoned for echocardiography and other tomographic methods. Even though a chest x-ray is still a frequently used screening procedure, particularly for acute diagnosis, it cannot provide important information about the presence of aortic pathology (von Kodolitsch et al. 2004; Hiratzka et al. 2010). Although changes in the ascending aorta often cannot be recognized in the mediastinal shadow, larger aneurysms in the descending thoracic aorta are often surprisingly well demonstrated (Hiratzka et al. 2010). On a sagittal noncontrast image, an isthmus stenosis may be demarcated as a notch-like dent in the aorta at the junction of the aortic arch and descending aorta, known as the “3 sign” of aortic isthmus stenosis. When one is assessing aortic isthmus stenosis radiographically, it should be borne in mind that the characteristic defects from the third to eighth ribs (notching on the underside of the ribs) usually appear only after the age of 8. These defects arise as a result of dilated intercostal arteries (known as Dock’s sign; Fig. 2.1-28). In general, a chest x-ray only has very limited diagnostic reliability, with a sensitivity of < 20% for detecting re-stenoses after correction of an aortic isthmus stenosis (Therrien et al. 2000).

Fig. 2.1–28a, b Posteroanterior (a) and lateral (b) radiographs in a 37-year-old patient with aortic isthmus stenosis. Rib defects can be seen as typical radiographic signs of aortic isthmus stenosis, as well as a notch in the descending aorta. Left ventricular hypertrophy is present as a secondary sign. A localized luminal constriction in the aorta can be seen in the area of the aortic isthmus on the lateral image.

Echocardiography: The aortic valve, ascending aorta and aortic arch with the origins of the supra-aortic branches can usually be well assessed with transthoracic echocardiography. It is important to carry out the examination from a suprasternal direction, which allows Doppler echocardiographic assessment of the gradient across the aortic isthmus stenosis (Warnes et al. 2008). Both Doppler echocardiography and invasive measurement of pressure gradients may underestimate the severity of an isthmus stenosis when there is good collateral flow (Warnes et al. 2008). Echocardiography has a sensitivity of 87% and a specificity of 78% for diagnosing recurrent stenoses of the aortic isthmus, while its sensitivity and specificity for diagnosing aneurysms in adults after correction of an aortic isthmus stenosis are only 29% and 98%, respectively (Therrien et al. 2000). It is important to carry out a search for malformations typically associated with aortic isthmus stenosis during the echocardiographic examination (Table 2.1-8) (Warnes et al. 2008). Transesophageal echocardiography is rarely used to identify an aortic isthmus stenosis.

Magnetic resonance imaging (MRI) or computed tomography (CT) with three-dimensional reconstruction: According to the current guidelines, all adults with aortic isthmus stenosis should undergo an initial examination with demonstration of the entire aorta and intracranial vessels (Warnes et al. 2008). MRI produces high-quality, high-resolution images that show the anatomy very well and it can also be used to quantify the flow in collateral vessels (Fig. 2.1-29) (Warnes et al. 2008). It provides all the information required for surgical correction, and it is also used for follow-up imaging examinations in patients who have undergone surgery for aortic isthmus stenosis. Several studies have confirmed that MRI can also be used in infants and neonates.

Fig. 2.1–29 Aortic isthmus stenosis on magnetic resonance imaging, with marked collateral formation and development of an aneurysm in the ascending aorta. Sagittal image with gadolinium contrast.

Fig. 2.1–30a, b Angiographic imaging of an aortic isthmus stenosis before (a) and after balloon angioplasty with successful stent placement (b, arrows).

Intracardiac catheter examination: Invasive diagnosis is by today’s standards only indicated in the context of interventional therapy for the aortic isthmus stenosis or to clarify complex cardiac defects, or in adults for preoperative exclusion of coronary heart disease (Fig. 2.1-30) (Warnes et al. 2008; Marek et al. 1995).

2.1.10.5 Treatment

Conservative treatment and general principles

Official recommendations are only available for control of arterial hypertension with medications. β-Blockers, angiotensin-converting enzyme (ACE) inhibitors and sartanes are the agents of choice (Warnes et al. 2008). In patients with aneurysm formation, β-blockers and vasodilators are particularly recommended (Warnes et al. 2008). The effect of statins is currently being tested for reducing atherosclerotic complications in adult patients with congenital heart defects (Krieger and Stout 2010). In accordance with the recommendations of the 36th Bethesda Conference, patients with significant re-stenosis or untreated isthmus stenosis, associated bicuspid aortic valve with aortic stenosis and those with dilation of the aortic root are advised not to take part in contact sports, isometric exercise, weightlifting, or sports involving abrupt starting and stopping (Graham et al. 2005). There has often been critical discussion of pregnancy in women with aortic isthmus stenosis. However, the published data suggest that relatively few complications occur and in particular that the risk of aortic dissection only appears to be slightly increased (Warnes et al. 2008; Pourmoghadam et al. 2002). According to the current guidelines, endocarditis prophylaxis is only indicated if surgical correction or stent placement has taken place during the previous 6 months, while uncomplicated and untreated aortic isthmus stenoses and uncomplicated re-stenoses do not require endocarditis prophylaxis (Warnes et al. 2008).

Correction of aortic isthmus stenosis

An indication for correction is basically established at the first diagnosis of aortic isthmus stenosis. In adults with previously undiagnosed aortic isthmus stenosis, an intervention is indicated according to the current guidelines if the peak-to-peak gradient over the isthmus stenosis on invasive measurement is ≥ 20 mmHg, or with smaller gradients if there is evidence on noninvasive imaging of severe isthmus stenosis with clear collateral formation (Warnes et al. 2008). If the noninvasively measured gradient already shows clear evidence of high-grade aortic isthmus stenosis, invasive measurement is not absolutely necessary.

Choice of technique

Surgical and percutaneous interventional procedures are available as alternatives for treating aortic isthmus stenosis. There are two indications for which one of these two options is clearly preferable. Firstly, surgical treatment for primary correction of aortic isthmus stenosis is currently recommended in neonates, since balloon angioplasty leads to re-stenosis or aneurysm formation in 10–70% of cases in this age group (Pourmoghadam et al. 2002). On the other hand, primary balloon angioplasty is also a good treatment option in this age group as well if the patient is at high surgical risk due to severe systemic diseases. Secondly, balloon angioplasty is regarded as the procedure of choice for the treatment of re-stenoses after corrected aortic isthmus stenosis in older children and young adults. In all other patients, there are currently no recommendations regarding the preference for a surgical or interventional correction procedure. However, in many centers surgical correction for aortic isthmus stenosis in adults is now only carried out when percutaneous interventional procedures do not appear appropriate (Warnes et al. 2008). It is recommended that the decision regarding which procedure to use should be made in a center for adults with congenital heart defects in collaboration between cardiologists, interventionalists and surgeons (Warnes et al. 2008). The choice of surgical technique is mainly based on the patient’s age (Table 2.1-11). In women who wish to have children, the advice tends to be to carry out primary treatment for aortic isthmus stenosis using a direct surgical approach with complete resection of the paraisthmic tissue (Warnes et al. 2008).

Table 2.1–11 Typical criteria for choice of the correction technique in patients with aortic isthmus stenosis.

Technique	Typical indication
End-to-end anastomosis/extended end-to-end anastomosis; Waldhausen subclavian flap plasty*	Age 0–2 years
Patch enlargement plasty*	Age 2–16 years
Tube prosthesis interposition	Age > 16 yearsLong or atypically locatedstenosesRe-stenosisLocal aneurysm formation
Balloon angioplasty/stent placement	Method of choice in adults with re-stenosis of the aortic isthmus(Warnes et al. 2008)

* Methods now only rarely used.

Surgical treatment for aortic isthmus stenosis

The following principles should be followed with surgical procedures. Firstly, to prevent re-stenoses from occurring, the resection or bridging of the aortic isthmus stenosis is always carried out at a wide distance from the immediate constriction. The aim here is particularly to achieve complete resection of scattered ductal tissue. Secondly, simultaneous continuous invasive arterial blood pressure measurement should be carried out at the radial artery and femoral artery intraoperatively. Thirdly, the mean arterial blood pressure in the upper half of the body should always be kept in the high normal range in order to avoid spinal cord ischemia and paraplegia. Fourthly, young adults and older patients are ventilated with a double-lumen tube so that the left lung can be immobilized for the duration of the surgical procedure.

End-to-end anastomosis

The technique for resection of aortic isthmus stenosis and end-to-end anastomosis described by Crafoord and Nylin (1945) is mainly used in small children and is currently regarded by many surgeons as the preferable correction method (Schmid and Asfour 2009; Karck et al. 2003). The technique can also be used with an “enlarged” end-to-end anastomosis to correct aortic arch hypoplasia. After mobilization of the aorta and ligation and transection of the ductus arteriosus, the aorta is adequately clamped well proximally and distally to the aortic isthmus stenosis. The stenotic area is resected and the distal and proximal aortic stumps are anastomosed. To keep the anastomosis as tension-free as possible, the aorta has to be adequately mobilized during this process. In the enlarged end-to-end anastomosis described by Amato et al. (1977), the small curvature of the aortic arch is further incised in order to enlarge a hypoplastic segment of the aortic arch. The distal segment of the aorta is connected to the lower side of the aortic arch, as in a side-to-end anastomosis (Fig. 2.1-31) (Amato et al. 1977).

Fig. 2.1–31 The various surgical techniques for correcting an aortic isthmus stenosis.

Indirect isthmus plasty (patch enlargement plasty)

The technique of isthmus plasty, in which the area of the aortic isthmus is enlarged using a patch, was introduced by Vossschulte in 1957 (Vossschulte 1956/1957). After proximal and distal clamping of the aorta, the vessel is split lengthwise over the area of the stenosis, followed by cross-suturing. In this process, a diamond-shaped or rhomboid patch of polytetrafluoroethylene (PTFE), also known as Gore-Tex or Teflon, is introduced using a continuous suture. This procedure is only suitable for very short stenoses in aortae with few degenerative changes. The advantages of the indirect isthmus plasty procedure are that there is no need to mobilize the aorta, the intercostal arteries are preserved and the technique is suitable for correcting re-stenoses. Disadvantages include residual ductal tissue, use of a synthetic material, and local aneurysm development, which occurs frequently even without the use of Dacron, which is associated with a particularly high risk for localized aneurysm formation (Schmid and Asfour 2009; Karck et al. 2003; von Kodolitsch et al. 2002).

Waldhausen subclavian flap plasty

In the subclavian flap plasty technique, developed by Waldhausen and Nahrwold in 1966, the left subclavian artery is used as a patch to bridge the aortic isthmus stenosis (Waldhausen and Nahrwold 1966). The left subclavian artery is removed distally, so that the blood supply to the left arm is ensured only if there is adequate collateral circulation. The advantages of this procedure are that it can be used with a long stenosis and that foreign material is avoided (Schmid and Asfour 2009). However, malperfusion with trophic disturbances or growth retardation in the left arm occurs in some patients. A subclavian steal phenomenon is also observed if the vertebral artery is not ligated. The technique is nowadays hardly used any more due to these complications.

Interposition of a tubular prosthesis

After resection of the stenotic aortic segment, a vascular prosthesis can be inserted. This consists of synthetic material such as Dacron, Teflon, or Gore-Tex; an aortic homograft is rarely used. The technique is used when an end-to-end anastomosis is not possible—e.g., with long stenoses or stenoses in atypical locations, when there is a prestenotic or post-stenotic aortic aneurysm, when the vascular wall has been lacerated during attempted end-to-end anastomosis, for primary correction of an aortic isthmus stenosis in adults, when the aorta has massive atherosclerotic changes, or in surgery for recurrences of the stenosis. As the tubular prosthesis used has a rigid diameter, this procedure should be used only in older adolescents, in order to avoid disparities between the prosthesis diameter and the aortic diameter.

Interventional therapy for aortic isthmus stenosis

Balloon angioplasty is an alternative to surgical treatment for isolated aortic isthmus stenosis. The procedure for dilating an aortic isthmus stenosis was first used in a postmortem case by Sos et al. (1979); in 1982, Singer et al. carried out balloon angioplasty successfully for the first time to treat re-stenoses in patients with aortic isthmus stenoses that had previously been operated on. Sperling et al. (1983) used balloon angioplasty in previously untreated aortic isthmus stenoses. Since then various research groups have reported on primary dilation of a previously untreated aortic isthmus stenosis, with varying success rates. The American Heart Association recommends this procedure only as the primary treatment option for adults with aortic isthmus stenosis in cases of re-stenosis, while a surgical approach is still recommended for longer re-stenoses and in patients with a simultaneous hypoplastic aortic arch (Warnes et al. 2008). To reduce the risk of re-stenosis, balloon angioplasty with stent placement can be carried out in patients whose body weight is over 25 kg (Warnes et al. 2008). In smaller patients, there are no advantages with primary stent placement. Of note, stents can be dilated further later on, therefore can be used in children in whom growth has not yet been completed. The indication for using stents to treat long stenoses is a matter of controversy and this is not currently recommended (Warnes et al. 2008).

Results in adults after corrected aortic isthmus stenosis

Successful correction of an aortic isthmus stenosis is currently regarded more as a palliative procedure, rather than as a cure for the condition (Krieger and Stout 2010). In a series of 248 patients who underwent successful surgery for an aortic isthmus stenosis, for example, a 25-year follow-up period showed a 12% mortality rate, with a mean age at death of 34 years (Maron et al. 1973). The main causes of death were coronary heart disease, sudden cardiac death, cardiac insufficiency, and stroke (Krieger and Stout 2010).

Typical long-term complications after correction of an aortic isthmus stenosis are listed in Table 2.1-12. Arterial hypertension and atherosclerotic complications are the main factors involved in an unfavorable long-term prognosis. When aortic isthmus stenosis is corrected later than the neonatal period, there is an increased risk for the development of chronic hypertension. This “paradoxical” or “rebound” hypertension may first occur immediately postoperatively, typically after an interval of 24–36 hours, with an increase in mean arterial pressure. This early hypertension is caused by activation of sympathicotonia and is best treated with β-blockers (Warnes et al. 2008). Secondly, the hypertension may occur at a late postoperative stage, with an increase in diastolic blood pressure in particular, even years after successful correction of the aortic isthmus stenosis. This type of hypertension is caused by activation of the renin–angiotensin–aldosterone system and occurs independently of re-stenosis of the aortic isthmus (Hager et al. 2007). Disturbed tissue elasticity in the aortic wall is also an important factor in the pathogenesis here.

Table 2.1–12 Typical long-term complications after correction of an aortic isthmus stenosis.

Complications	Frequency (after Krieger and Stout 2010)(%)
Persistent arterial hypertension or arterial hypertension developing during subsequent course	Correction during childhood: < 5%Correction in adults: > 25%
Re-stenosis of the aortic isthmus	Correction in neonates: 2.4–5.5%Correction at a later age: < 1%
Aortic aneurysm/aortic dissection	5–16%

Re-stenosis is defined as the recurrence of a peak-to-peak gradient ≥ 20 mmHg, and is often associated with symptoms of uncontrolled arterial hypertension. Re-stenosis may remain asymptomatic for a long period and then can only be diagnosed using a targeted examination. The main risk factor for re-stenosis developing is correction of the aortic isthmus stenosis in neonates and children aged under 1 year. Re-stenosis is an important risk factor for recurrent arterial hypertension. A second procedure is indicated when the peak-to-peak gradient is ≥ 20 mmHg, or with smaller gradients if hypertension cannot be controlled with drugs or collateral circulation circuits have developed (Krieger and Stout 2010; Warnes et al. 2008). The treatment primarily involves the use of interventional procedures (Warnes et al. 2008). Successful elimination of the re-stenosis usually also leads to a reduction in blood pressure (Krieger and Stout 2010).

Fig. 2.1–32 Bicuspid aortic valve is an independent risk factor for the development of aneurysms, particularly in the area of the ascending aorta (Aydin et al. 2011). Patients who have undergone successful correction of an aortic isthmus stenosis, particularly with a bicuspid aortic valve, always require lifelong follow-up with imaging including the ascending aorta (von Kodolitsch et al. 2002; 2010).

Fig. 2.1–33 Anatomic types of aneurysm development in the aorta after primary correction of an aortic isthmus stenosis.

Table 2.1–13 Aneurysm development after surgical correction of aortic isthmus stenosis (von Kodolitsch et al. 2002).

– = information not available.

Aneurysm formation is another complication and is associated with a high mortality rate (Table 2.1-13) (von Kodolitsch et al. 2002, 2010; Oliver et al. 2004; Aydin et al. 2002). Aneurysms may develop independently of the technique used, the patient’s age and the success of the aortic isthmus stenosis correction. Local aneurysms have even been observed in 8% of cases after balloon angioplasty (Fawzy et al. 2004). The development of local aneurysms is noted postoperatively particularly after patch enlargement plasty (Karck et al. 2003), while aneurysms in the ascending aorta appear particularly in patients with a bicuspid aortic valve (Aydin et al. 2002; von Kodolitsch et al. 2002). Depending on the pathological mechanism and location, true, false, and dissecting aneurysms may occur (Figs. 2.1-32 and 2.1-33). Treatment for local aneurysms is generally surgical, although it can also be carried out using stent grafts in individual cases (Warnes et al. 2008).

Follow-up

Due to the high complication rates and even higher mortality after correction of aortic isthmus stenosis, the affected patients need lifelong follow-up with cardiologists with expertise in caring for adult patients with congenital heart disease (Schmaltz et al. 2008; Krieger and Stout 2010; Warnes et al. 2008). Follow-up examinations should be carried out at least at annual intervals. At each follow-up examination, a physical examination should be carried out with measurement of blood pressure and an ECG recording (Krieger and Stouth 2010). Measurement of blood pressure in both arms with the patient supine, simultaneous palpation of the radial and femoral pulse, and auscultation at precordium and left paravertebral position to detect any re-stenosis are obligatory elements in the physical examination (Krieger and Stout 2010). Ophthalmoscopy of the fundus of the eyeball to note any chronic hypertension, are also recommended at each follow-up consultation.

Measurement of blood pressure over 24 hours and ergometry testing to identify exercise hypertension are recommended by many authors, but these are not obligatory. Imaging of the entire aorta every 2–5 years is recommended (Krieger and Stout 2010).

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2.2 Diseases of the pulmonary arteries

2.2.1 Pulmonary artery embolism

Clinical findings: Edda Spiekerkötter and Thomas Zeller

Anatomy of the pulmonary arteries: Reinhard Putz

Conservative treatment: Edda Spiekerkötter and Thomas Zeller

Endovascular treatment: Thomas Zeller

Surgical treatment: Matthias Thielmann

2.2.1.1 Anatomy of the pulmonary arteries

The right and left pulmonary arteries originate in a shallow bifurcation from the pulmonary trunk, which is approximately 5 cm long and 3 cm wide and lies in an oblique cranial position. The start of the trunk is marked by the pulmonary valve, which like the aortic valve is formed by three semilunar cusps. The three pockets formed in this way do not lead to any distension of the initial part of the trunk, however, since the systolic pressure in the pulmonary system is much lower than in the aorta. The walls of the large pulmonary arteries are accordingly slightly less robust comparatively and only contain a strong elastic fibrous lattice instead of an internal elastic membrane.

The trunk initially lies anterior to the ascending aorta and then ascends on the left side of it where it then divides under the aortic arch, which is then already located outside of the pericardium. The slightly longer and slightly wider right pulmonary artery passes behind the ascending aorta and superior vena cava, but in front of the right mainstem bronchus and esophagus, in an oblique dorsal course to the hilum of the right lung. The left pulmonary artery also crosses at a slightly oblique angle on the short path into the hilum of the left lung. Just after the division of the two pulmonary arteries, the ligamentum arteriosum connects the left pulmonary artery with the inner contour of the aortic arch. This “ligament,” which has highly variable alignments, is the rudimentary residue of the fetal ductus arteriosus (Fig. 2.2-1).

Fig. 2.2–1 Anterior view of the pulmonary arteries.

Before the division into the lobar branches, the trunk of the right pulmonary artery reaches its furthest cranial point in the hilum; on the left side, this occurs at the left mainstem bronchus. The primary branches of the two pulmonary arteries cross the bronchial tree ventrally and then enter the pulmonary lobes centrally along with the bronchi. Along with the bronchi, they divide further into the segmental arteries, which also lie centrally.

2.2.1.2 Clinical picture

The pathoanatomic correlate for pulmonary artery embolism is occlusion of the pulmonary arteries by thrombi (or rarely by fat, air, foreign bodies, tumor, or amniotic fluid) from another vascular region. The extent of the vascular obstruction and underlying cardiopulmonary function determine the severity and thus the mortality of pulmonary artery embolism.

Acute pulmonary embolism is the third most frequent cardiovascular disease; in the U.S. alone, it has an annual incidence of approximately 500,000 and is responsible for 200,000 deaths per year. In Germany, pulmonary embolism has a reported incidence of approximately 100,000 per year (one to three per 1000 inhabitants), with 20,000–30,000 of these cases having a fatal course, and it affects 0.1–0.4% of hospitalized patients, 12–14% of postoperative deaths and 45–90% of all deaths within 2 h.

Massive and fulminant acute pulmonary embolism (Grosser stages III and IV) as a sequela of deep venous thrombosis is life-threatening and has an overall mortality rate of more than 30%, with 50% of deaths occurring within the first 30 min, 70% within the first hour, and more than 85% within the first 6 h after the onset of symptoms. Particularly in patients requiring resuscitation, the prognosis without immediate revascularization treatment is unfavorable. Rapid diagnosis and appropriate therapy are therefore decisive for saving the patient’s life. Developments in fibrinolytic and percutaneous treatment have increasingly pushed surgical treatment for acute massive and fulminant pulmonary embolism into the background.

For chronic recurrent pulmonary embolism, see section A 2.2.2.

2.2.1.3 Diagnosis

Clinical findings

The clinical probability of pulmonary embolism and deep venous thrombosis is estimated as described above.

ECG

Right axis deviation

Sinus tachycardia: 50%

ST segment changes (particularly V1–V4): 40%

Right bundle-branch block: 15%

S_IQ_III type: 15%

P pulmonale: 5%

Laboratory findings

Blood gas analysis (BGA): hypoxemia despite hyperventilation (Po₂ ↓, Pco₂ ↓)

d-dimers (microplate ELISA, VIDAS ELISA, Simpli-RED®):

– Negative findings (< 500 μg/L) practically exclude pulmonary embolism; i.e., in 30% of patients with emergency admission, but fewer than 10% of inpatients, pulmonary embolism can be excluded using d-dimer assessment.

– Caution: d-dimers are also raised in infection, inflammation, carcinoma, status post surgery, cardiac insufficiency and renal insufficiency, acute coronary syndrome, pregnancy, and sickle-cell crisis.

– Troponin: evidence of hemodynamically significant pulmonary embolism, right ventricular enlargement, right cardiac ischemia

Coagulation tests:

– Protein C

– Protein S

– Angiotensin III

– APC resistance

– Rheumatism serology, including anticardiolipin

Chest x-ray

Nonspecific changes include:

Atelectasis/infiltrate: 80%

Pleural effusion: 50%

Elevation of the diaphragm (unilateral): 30%

Vascular asthenia: 20%

Prominent pulmonary artery segment: 15%

Hilar vessel truncation (Westermark sign): 10%

Wedge-shaped solidification near the pleura (pulmonary infarction): 10%

An unremarkable chest x-ray does not exclude pulmonary embolism.

Diagnosis of deep venous thrombosis

B-image ultrasound with compression testing, color duplex ultrasonography (see section B 1.2, diagnosis of DVT)

Phlebography

Table 2.2–1 Pathophysiology of pulmonary embolism.

Pulmonary artery obstruction → afterload increase for RV → walltension ↑, RV ischemia, RV decompensation, acute cor pulmonale →RV output ↓, RV volume ↑, septal deviation → LV preload ↓, cardiac output ↓ → RV coronary perfusion ↓ → right heart failure

Inhomogeneous perfusion → wasted ventilation → hypoxemia

Released mediators (thromboxane A2, serotonin, fibrinopeptides, leukotriene) → vasoconstrictio

RV, right ventricle; LV, left ventricle.

Table 2.2–2 Clinical probability of pulmonary embolism (adapted from Perrier).

High (80–100%)	Risk factor present, otherwise unexplained dyspnea, pleuritic pain, gas exchange disturbance or abnormalities on chest x-ray
Intermediate (20–79%)	Neither high nor low probability of pulmonary embolism
Low (0–19%)	No risk factors present, clinical symptoms and findings explicable by other causes

Table 2.2–3 Severity of pulmonary embolism (adapted from Grosser).

BP, blood pressure.

Echocardiography (transthoracic echocardiography, transesophageal echocardiography)

Acute right ventricular load:

– Dilated, hypokinetic RV

– Raised RV/LV ratio

– Deviation of the intraventricular septum in LV

– Dilated proximal pulmonary arteries

– Regurgitation via the tricuspid valve (jet: 2.5–2.8 m/s)

– Dilated inferior vena cava without collapse on inspiration

Evidence of an embolus in transit

Exclusion of differential diagnoses:

– Myocardial infarction

– Valvular insufficiency

– Hypovolemia

– Endocarditis

– Aortic dissection

– Pericardial tamponade

Ventilation–perfusion scintigraphy

Only applicable with normal findings (15%) → exclusion of pulmonary embolism, high-probability finding (13%) → treatment. When ventilation–perfusion scintigraphy is not diagnostic—i.e., in approximately 70% of cases—further diagnostic procedures are necessary.

Spiral CT

High sensitivity (94%) and specificity (94%) in embolism of the main trunk of the pulmonary artery and segmental arteries

Evidence of right ventricular dilation

It is recommended that spiral CT should be used in combination with the clinical findings, laboratory test data, and compression ultrasonography. The advantage of spiral CT is that it is not invasive and allows differential diagnoses to be excluded.

Magnetic resonance imaging (MRI)

Imaging of the central vessels, with sensitivity and specificity comparable to those with spiral CT.

Advantages: noninvasive, exclusion of differential diagnoses, contrast administration not necessary.

Disadvantages: long examination time (with breathing pauses).

Pulmonary artery catheter

Complete data on pressure conditions and hemodynamics

Increased PAP_mean > 25 mmHg: obstruction of pulmonary bloodstream in only 50%

Increased PAP_mean > 40 mmHg: only with a previously preloaded right ventricle

Caution: bleeding complications in planned lysis. Pulmonary angiography is the gold standard for massive and submassive pulmonary embolism and planned treatment (lysis). Definite signs include vascular abruption and filling defects. Catheter fragmentation of thrombi can be carried out in the same session if appropriate.

2.2.1.4 Treatment

Conservative treatment

General measures

Bed rest

Oxygen administration: nasal probe, oxygen glasses or mask up to 10 L O₂/min. When there is hypoxemia despite O₂ administration (SaO₂ < 80%): intubation and ventilation

Analgesia and sedation: morphine 5 mg i.v./s.c., diazepam (e.g., Valium®) 5–10 mg i.v.

Heparin 5000–10,000 IU i.v. as a bolus, followed by therapeutic heparinization (20 IU/kg/h) aiming for 1.5–2.5 times partial thromboplastin time (PTT)

Initial care

Volume administration:

– Caution when there is severe right ventricular dysfunction; 500 mL “fluid challenge” (e.g., HAES-steril® 10%) with cardiac output ↓ and normal blood pressure (BP)

Catecholamines:

– Mild hypertension: dobutamine (Dobutrex®) 2.5–12.0 μg/kg/min. Effect: cardiac output ↑, oxygen transport ↑, peripheral vasodilation (β₂ receptors), peripheral vascular resistance ↓, possible deterioration of ventilation-perfusion mismatch with Po₂ ↓

– Severe shock: norepinephrine (Arterenol®) 0.05–0.30 μg/kg/min. Effect: mean arterial pressure ↑ (α₁ receptors), right ventricular coronary perfusion ↑, right ventricular ischemia ↓, cardiac output ↑ (β₁ receptors)

Systemic fibrinolytic therapy

Indications. Massive pulmonary embolism (it is currently being debated whether this type of treatment can also be used in submassive pulmonary embolism—i.e., when there is right ventricular dysfunction without shock and with no contraindications for lysis). The pulmonary embolism should be confirmed by CT in submassive pulmonary embolism before lysis treatment is started, or there should be a high clinical likelihood of acute cor pulmonale (TTE, TEE) without prior cardiorespiratory disease.

Contraindications. The same contraindications as those for systemic lysis apply:

Absolute:

– Active internal bleeding

– Spontaneous intracranial bleeding

Relative:

– Larger operation

– Pregnancy, labor

– Organ biopsy

– Puncture of noncompressible vessels < 10 days

– Cerebral ischemia < 2 months

– Gastrointestinal bleeding < 10 days, severe trauma < 15 days

– Neural or ophthalmic surgery < 1 month

– Severe hypertension, BP_syst > 180 mmHg, BP_diast > 110 mmHg

– Bacterial endocarditis

– Diabetic hemorrhagic retinopathy, thrombocytes < 100,000/μL

– Status post resuscitation

Procedure:

rt-PA (Actilyse®): short-term lysis: 10 mg bolus i.v., 90 mg over 2 h, bolus lysis: 50 mg bolus i.v., second bolus after 30 min, always with simultaneous full heparinization

Urokinase (Actosolv®, Corase®): short-term lysis: 1 million IU as bolus i.v., 2 million IU over 2 h, bolus lysis: 3 million IU as a bolus i.v., always with simultaneous full heparinization

Streptokinase (Streptase®): short-term lysis: 1.5 million over 30 min, 1.5 million/h over 3–4 h, repetition after 24 h possible

Limitations of systemic fibrinolytic therapy. The Management Strategies and Prognosis in Patients with Pulmonary Embolism (MAP-PET) registry has shown that 40% of patients with acute pulmonary embolism have at least one contraindication against fibrinolytic therapy. In the International Cooperative Pulmonary Embolism Registry (ICOPER), it was clearly shown that 17.4% of the patients included died within 90 days; 21.7% of patients who received fibrinolytic therapy had severe bleeding complications, and 3% developed intracerebral hemorrhage. It must therefore be assumed that fibrinolysis treatment actually has a higher complication rate than has been postulated in controlled and therefore fairly selective and artificial individual studies. Some 15–25% of patients who receive lysis have only partial dissolution of the emboli in the pulmonary vascular circulation. However, persistent pulmonary hypertension after pulmonary embolism is associated with increased mortality. Meneveau et al. (2003) showed that the “residual embolism burden” after incomplete fibrinolytic reopening of the pulmonary vascular bed is an independent prognostic factor for the long-term results in these patients. When there was a residual obstruction of more than 30% of the pulmonary vascular bed, the multivariate analysis showed a relative risk of 2.2, with a 95% confidence interval of 1.7 to 2.7, for long-term mortality. While it was previously assumed that chronic thromboembolic pulmonary hypertension only develops in very few patients after acute pulmonary embolism, Meneveau et al. suggest that the numbers of patients affected may have been underestimated and propose more careful follow-up for patients with residual obstruction so that they can then undergo pulmonary thromboendarterectomy if appropriate. A flow model (Fig. 2.2-2) may provide a flow-physiological explanation for the incomplete thrombolysis. Proximal to the occlusion, there is turbulence with diversion of the blood flow into nonoc-cluded vascular segments, so that the contact between the thrombolytic agent and the thrombus is often only inadequate. Tabut et al. (2002) thus confirmed in a meta-analysis of nine randomized and controlled studies including 461 patients that fibrinolytic therapy provides no advantages in comparison with intravenous heparin administration in unselected patients, although it is associated with an increased risk of severe bleeding complications.

Fig. 2.2–2 Flow model for flow-physiological explanation of incomplete systolic thrombolysis. Turbulence proximal to the occlusion (B) and diversion of the blood flow into the unoccluded left pulmonary artery. The turbulence in front of the thrombus leads to poor contact between the thrombolytic agent and the thrombus (Uflacker 2004). RUL, right upper pulmonary arteries; RI, right inferior pulmonary arteries; B, thrombus; T, main pulmonary artery trunk; LUL, left upper pulmonary arteries; LLL, left lower pulmonary arteries.

Endovascular therapy

Indications for endovascular therapy

The same indications apply as for systemic lysis treatment—massive pulmonary embolism in which more than 50% of the pulmonary circulation is obstructed, with the patient showing hemodynamic instability.

Contraindications against endovascular therapy

In contrast to systemic lysis, there are no real contraindications here. Any patient, including those in resuscitation conditions, can receive percutaneous endovascular treatment.

In principle, the general contraindications against the use of iodine-containing radiographic contrast media apply (e.g., hyperthyroidosis, previous severe reaction to contrast medium, advanced renal insufficiency), with no option available for using an alternative contrast agent (e.g., gadolinium in DSA-capable x-ray equipment).

Patient preparation

As this is usually an emergency procedure, patients must have the basic aspects of the planned procedure explained to them if they are conscious, and the legally prescribed waiting period of 1 day does not need to be observed.

Medication

With unstable hemodynamic indices, all patients have already received therapeutic heparinization. Administration of platelet aggregation inhibitors has not been confirmed in controlled studies, but is recommended (with an intravenous bolus dose of 50 mg acetylsalicylic acid). After placement of the femoral sheath, a heparin bolus of 2500– 5000 IU is administered, depending on the patient’s body weight and the expected length of the procedure.

Access route

The most frequently used access route is transvenous femoral access, or less frequently brachial access via the basilic vein or cephalic vein. Jugular access is reserved for special large-lumen catheter systems.

Femoral access

Femoral access is the standard route. The femoral artery pulse can serve for guidance; the femoral vein lies approximately 1.0–1.5 cm medial to the artery. Due to the potential need for local lysis, detailed attention should be given to ensure that the artery is not punctured. It may be helpful to carry out the puncture with fluoroscopy, as the artery can be identified radiographically if there is calcification of the arterial walls. The size and length of the sheath depend on the selected interventional technique and can vary from 5F to 11F and from 11–90 cm, respectively. Reaching the right ventricle or pulmonary arteries is easiest using a flow-directed balloon-tipped catheter that has a guidewire lumen. After the flow-directed balloon-tipped catheter has been positioned in the right ventricle, the guidewire (0.035-inch Glidewire®, Terumo) is introduced, and the flow-directed catheter is exchanged over the guidewire for a pigtail catheter (5F or 6F) for diagnostic angiography.

Brachial access

A 5F or 6F sheath is placed in the basilic vein or alternatively in the cephalic vein, and a pigtail catheter is advanced into the right ventricle or main pulmonary arterial trunk for diagnosis, as in femoral access.

Preinterventional angiography

Either conventional angiography or DSA (15 mL/s contrast injection at 600 psi, total amount 30 mL) is carried out via the pigtail catheter. It is possible to distinguish between submassive and massive pulmonary embolism using the Miller score. With a maximum score of 34 (central obstruction of the right pulmonary artery, 9 points; left pulmonary artery, 7 points; peripheral obstruction of the upper, middle, and lower lobe of the lung, each with no flow, 3 points; severely reduced flow, 2 points; moderately reduced perfusion, 1 point), a score > 10 signifies a massive pulmonary embolism.

Fig. 2.2–3a, b Angiographic image of an embolism (arrow) in the pulmonary artery supplying the left lower lobe, (a) 15 min after 8-mm PTA and 15 mg rt-PA locally as a bolus (b).

Fig. 2.2–4a, b (a) Embolism in the left main pulmonary artery trunk (MRI). (b) Image 6 months after local lysis treatment.

Interventional techniques

Various catheter-based interventional techniques are available, although none of these except local thrombolysis can be regarded as generally valid.

Local thrombolysis

Only some 60–70% of patients with massive pulmonary embolism are able to undergo lysis treatment; the remaining 30–40% have contraindications such as a recent history of surgery, trauma, or carcinoma. In local catheter thrombolysis, a 5F Cragg-McNamara lysis catheter with side holes over a length of 5–10 cm (ev3 and Boston Scientific, etc.) is placed in the thrombus over a hydrophilic-coated 0.035-inch guidewire. As a lytic agent, either urokinase (4500 IU/kg body weight as a bolus, followed by 2000 IU/kg body weight/h) or rt-PA (25–50 mg as a bolus, followed by 25–50 mg/h) is used. When rt-PA is used, heparin with PTT guidance needs to be infused to reduce reocclusion rates. The patient either remains in the catheter laboratory so that the success of the lysis treatment can be documented with serial angiography or, if there is adequate circulatory stability, can be returned to the intensive care unit, where lysis can be continued until hemodynamic improvement is seen.

According to the International Cooperative Embolism Registry (ICOPER), relevant bleeding complications occur with lysis treatment in up to 21% of cases, and intracranial hemorrhage in up to 3% of cases.

Ultrasound-enhanced local thrombolysis. For this procedure, a catheter with several ultrasound-emitting probes attached to its sides (EkoSonic™; Ekos Corporation, Bothell, Washington, USA) is placed in the pulmonary artery and the thrombolytic agent is infused via the catheter during the application of ultrasound waves. The ultrasound waves are intended to separate the fibrin bridges and thus allow better penetration of the drug into the thrombus, shortening the time required for thrombolysis. Controlled studies on the technique are in progress.

Mechanical catheter thrombus fragmentation and local catheter lysis

In central obstruction of the major pulmonary artery trunk, simple mechanical thrombus fragmentation with the guidewire or by rotating the pigtail catheter used for diagnostic angiography in the thrombus can already lead to significant hemodynamic improvement. Mechanical thrombus fragmentation can also be achieved using balloon dilation. However, the contrary effect of further hemodynamic deterioration can occur due to shifting of the thrombi into the peripheral vascular region (Fig. 2.2-5). Mechanical thrombus fragmentation should therefore always be combined with subsequent local lysis over a 5–10-cm sidehole catheter.

Thrombus aspiration

Pulmonary thrombus aspiration was first reported by Greenfield et al. in 1971 using a 10F aspiration catheter. This system is currently the only aspiration catheter approved by the U.S. Food and Drug Administration (FDA). It is now possible to use large-lumen catheters (minimum 8F), which are available in various configurations. These allow clots to be aspirated even from the segmental pulmonary branches (with suction using a 50-mL syringe).

Fig. 2.2–5a, b Dispersion of small thrombi into the peripheral branches of the pulmonary artery after mechanical fragmentation.

Mechanical and rheolytic catheter thrombectomy

No mechanical thrombectomy systems are currently approved for use in patients with major pulmonary embolism. Ideally, the system should be very flexible, allowing easy passage into the right heart and pulmonary artery system with high suction, with no risk of damaging the pulmonary arteries.

Various systems that are used on an off-label basis at the moment, such as the AngioJet™ (Possis, Fig. 2.2-6), Amplatz Clot Buster™ (BARD), and Hydrolyser™ (J&J Cordis), were not designed for use in vessels with large lumina and therefore have to be used in combination with local fibrinolytic therapy.

Potential side effects of these catheter systems include mechanical hemolysis, macroembolization, and microembolization. According to the current literature, only 5% of patients with a major pulmonary embolism are treated with a mechanical catheter thrombectomy system. Thrombectomy catheters that have been used to date are: