The development of the blood vessels is correlated with two main processes: vasculogenesis and angiogenesis. Often, the two terms are used interchangeably. However, they describe different developmental processes. Vasculogenesis represents new blood vessel formation. It starts on the eighteenth day of embryonic development when specific cells of the intraembryonic mesoderm differentiate into angioblasts. They agglutinate to form small vesicles. Furthermore, the vesicles fuse into tubes and establish the circulatory system of the embryo [
55]. The second process, angiogenesis, consists of budding and sprouting at the very end of the initial vessels of the embryo. From this point on, the two processes coexist with the splitting or fusion of the new blood vessels, or even forming anastomoses such as those at the cerebral level. These processes can be the basis for the occurrence of a vascular malformation such as ectopic origin, duplication, or fenestration [
55,
56].
4.1. Embryological Development of Aortic Arches—Starting Point in the Elucidation of Great Vessel Malformations
Vasculogenesis plays a prominent role during heart development because it is the primary process involved in forming lateral endocardial tubes. Lately, they will fuse to form the primary cardiac tube (PCT). The cranial segment of the primary cardiac tube will form the two ventral aortas that loop dorsally [
55,
57,
58].
The paired dorsal aortas right (RDA) and left (LDA), are born through the same vasculogenesis process. The angioblasts develop in the dorsal mesenchyme of the paraxial mesoderm on either side of the notochord. The cranial growth and the cranio-caudal folding of the embryo are responsible for the proximity of the dorsal aortas to the primitive heart tube. This convergence process, along with the looping of the two ventral aortas, allows the connection between the two structures, resulting in the first pharyngeal arch artery [
57,
58,
59,
60,
61].
During the fourth week, the dorsal aortas fuse next to the fourth thoracic to fourth lumbar somitic segments and form a single arterial tube. In the cranial segment, they remain separated, attached to the aortic sac by aortic arches [
55,
57,
58,
59,
60,
61,
62].
Between the fourth and fifth week, four more aortic arch pairs named 2 to 6 develop from the aortic sac. In fact, the fifth pair does not develop [
55], or it completely regresses very early [
57]. The development of the aortic arches is connected with the development of the pharyngeal arches, and, in addition, the arterial structures are found inside the mesenchyme of the pharyngeal arches [
57]. The aortic arches, the same as pharyngeal arches, do not coexist. They are formed starting with the cranial segment towards the caudal one, and, while one is forming, the previously appeared one regresses [
55,
57,
58,
59,
60,
62].
The first aortic arch is the primordial connection between the aortic sac and dorsal aorta. It will regress starting from the twenty-eighth day, coexisting briefly with the second arch. Only a few parts persist as segments of the maxillary artery [
60,
62].
The second aortic arch forms on the twenty-sixth day and regresses on day twenty-nine. Its remnants form segments of the stapedius artery [
59,
62].
The appearance of the third, fourth, and sixth aortic arches occurs approximately in the same period. The third and fourth pairs appear on day twenty-eight, while the sixth pair appears on the twenty-ninth day. On the thirty-fifth day, the segment of the dorsal aorta between pairs three and four, called the carotid duct, disappears bilaterally. Thus, the third aortic arch will create the only connection between the aortic sac and the cranial segment of the two dorsal aortas. Consequently, it will supply blood to the cephalic extremity of the embryo [
55]. Remnants of the third aortic arch form the common carotid arteries and the proximal segment of the internal carotid arteries. The cranial segment of the dorsal aorta persists bilaterally as the cranial segment of the internal carotid arteries. The external carotid arteries arise from the common carotid arteries following the angiogenesis process [
55,
57].
After the regression of the carotid duct, the fourth aortic arch remains connected with the distal segment of the corresponding dorsal aorta. The two seventh cervical intersegmental arteries (SCIA) are formed at the junction of the two dorsal aortas. The heart migration associated with the elongated embryo is responsible for the rising of the origin of these branches to maintain the correspondence with the upper limb somites. By the seventh week, the segment of the RDA between the origin of the right SCIA and the place of fusion with the LDA degenerates. The remaining segment of the right dorsal aorta connects the right fourth aortic arch to the right SCIA to form the right subclavian artery. The initial segment of the fourth aortic arch and the adjacent aortic sac structures will form the brachiocephalic artery [
55,
58,
59,
62]. On the left side, the fourth aortic arch remains connected to the aortic sac. It gives rise to the ascending aorta, and the cross and the proximal segment of the descending aorta. The distal segment of the descending aorta is formed by a fusion between the LDA and RDA. The left SCIA builds the left subclavian artery to supply the left upper limb [
55,
59,
62].
The intersegmental arteries are born through the process of vasculogenesis. They appear in the somitic mesenchyme and further connect to the ipsilateral dorsal aorta. Like the somites, they have segmental organization: cervical, dorsal, lumbar, and sacral. The cervical intersegmental arteries form a complex anastomose centered by a longitudinal branch. In order to become the vertebral artery, it loses connection with the ipsilateral dorsal aorta, maintaining the connection with the seventh cervical intersegmental artery. This way, the origin of the vertebral artery corresponds to the subclavian artery [
55].
The sixth aortic arch appears from the proximal part of the aortic sac and connects to the paired dorsal aorta caudally by the fourth aortic arch. It is the last to develop but the first to remodel—the septation and rotation of the outflow tract cause the late process. The development of the sixth aortic arch is not symmetric. On the right side, the aortic arch elongates due to the rotation process and loses connection with RDA while it connects with the artery arising from the pulmonary primordium [
4,
57,
61,
62]. On the left side, the connection between the sixth aortic arch and LDA persists during intrauterine life as the ductus arteriosus or Botalli’s duct. Eventually, it obstructs after birth, and its remains form the arterial ligament. Ventrally, it sprouts and extends towards the pulmonary bud. In order to form the pulmonary artery, it anastomoses with the vessels developed from the mesenchyme around to the bronchi [
57,
61]. Schoenwolf GC et al. [
55] suggest that the main origin of the pulmonary artery is, in fact, the fourth aortic arch. During development, it loses its connection with the fourth aortic arch, but not before forming a connection with the sixth aortic arch.
4.2. The Complex Developmental Defects—Starting Point for an Original Morphological Classification
From the perspective of its course, ARSA can be situated retroesophageally (80–84%), between the esophagus and trachea (12.7–15%), or pretracheally (4.2–5%) [
63,
64,
65]. At the same time, variants in the origin of the right common carotid artery and, respectively, of the right vertebral artery frequently accompanied ARSA. The bicarotid trunk, also known as truncus bicaroticus, has an incidence of 5%, the higher rates (4–20.6%) recorded in association with ARSA [
65,
66]. RVA often emerges from the right aberrant subclavian or common carotid artery. Only a few cases in which RVA originates in the left vertebral artery or directly in the aortic arch are reported [
65]. Considering these facts, we propose an original classification that includes various morphological aspects, with the essential point represented by the ARSA trajectory. Compared to Adachi and Williams [
67], our classification is more morphologically and clinically oriented:
Type I—retroesophageal course;
Type II—intertracheo-esophageal course;
Type III—pretracheal course;
a—origin of right vertebral artery from the aberrant right subclavian artery;
b—origin of right vertebral artery from the right common carotid artery;
c—origin of right vertebral artery from the aortic arch;
d—origin of right vertebral artery from the left vertebral artery;
B—presence of bicarotid trunk;
K—presence of Kommerell diverticulum.
4.3. Summary of Evidence
This systematic review included 47 case reports and case series with a total of 51 patients diagnosed with ARSA. Our main goal was to identify the morphological aspects of the lusoria artery, as well as the associated malformations. In accordance with the morphological types encountered, we propose a new classification system; the cases selected in the screening stage were entered in this classification. Secondarily, we analyzed the demographic distribution of the selected patients.
After analyzing the recorded data (
Table 1), we identified a higher incidence of ARSA in women at 62.74% (32 out of 51) compared to men at 37.25% (19 out of 51). These data are in accordance with those presented by Polguj et al. [
68], but the percentage difference recorded between the two sexes is smaller (55.3% vs. 44.7%).
The demographic analysis showed a relatively uniform distribution with a peak in the “44 to 57 years” and “58 to 71 years” age groups. These data are consistent with the distribution of specific symptoms with a high weight in the same age ranges. The non-specific symptomatology predominates in the “58 to 71 years” interval with minimum values in the “16 to 29 years” and “30 to 43 years” intervals.
Our research proves that the typical course of ARSA is retroesophageal (49 out of 51). Only two cases reported by Chen et al. [
14] presented a pretracheal trajectory. Natsis et al. [
64] mentions in his dissection study the presence of the intertracheo-esophageal path in 1 out of 6 cadavers without identifying the pretracheal path. ARSA is relatively frequently associated with Kommerell’s diverticulum, which can be found in 20–60% of the subjects who present this malformation, while the
truncus bicaroticus is rarely found [
69]. In our review, 15 out of 51 cases report the presence of Kommerell’s diverticulum, while the bicarotid trunk we identified only in seven cases. In a single case reported by Downey et al. [
47], the association between the bicarotid trunk and the Kommerell diverticulum was identified. In the vast majority of cases, we identified the origin of the right vertebral artery to be in the ARSA (44 out of 51). In two cases, we found its origin in the aortic arch and five other cases in the ipsilateral common carotid artery. In the selected time interval, no case was reported in which the origin of the right vertebral artery was in the left vertebral artery. We present the cases frequencies included in our new classification in tabular form (
Table 6).
Computed tomography angiography with 3D reconstruction techniques represents the gold standard for diagnosing ARSA, having a sensitivity of 100%. The transthoracic echocardiography detects ARSA in 92 out of 100 patients, while chest radiography identifies this malformation in only 20% of cases [
68]. New techniques such as Photon-Counting CT ensure good image quality and an excellent contrast-to-noise ratio. In this context, patients with renal failure can benefit from the investigation, reducing the risks to a minimum, by reducing the amount of contrast material administered [
70].
The occurrence of clinical manifestations varies between 7–10% [
68] and 30% [
44]. They are various but, at the same time, non-specific, with dysphagia (hence the name dysphagia lusoria), dyspnea, retrosternal pain, chest pain, or weight loss predominating. Our review is in accordance with the clinical aspects mentioned; the symptomatology is dominated by dysphagia (24 out of 51 subjects). Only 4 out of 51 patients report weight loss, being overtaken by chest pain (5 out of 51) and asymptomatic patients (7 out of 51). In addition, symptoms are the prerogative of adulthood, with symptoms appearing at approximately 48 years, with significant differences between men (44.9 years) and women (54 years). Several authors such as Osiro et al. [
71] and Mochizuki et al. [
72] associate ARSA with hemodynamic changes at the level of the upper limb, as well as at the vertebro-basilar level. The “subclavian steal syndrome” is clinically characterized by both central and peripheral ischemic and neurological phenomena.
Moreover, the morphological aspect of ARSA, such as the trajectory and coexisting vascular malformations (
truncus bicaroticus), also determines the age of the onset of symptoms [
69]. The predominance of wheezing, stridor, and recurrent lung infections are the prerogative of small children and are primarily due to the histological aspect of the trachea, which is easily compressible [
73]. According to Polguj et al. [
68], atherosclerosis is the main factor correlated with the appearance of symptoms in adults. In support of this statement, we point out that there is a concordance between the age of onset of ARSA symptoms and the age of onset of symptoms caused by atherosclerosis. This agreement is achieved both in the case of women, who are protected by the secretion of estrogen hormones, and in men.
The treatment must be staged and adapted to the morphological and clinical aspects. Follow-up is recommended for asymptomatic patients. Patients with minor and moderate clinical manifestations require lifestyle changes in terms of physical effort and eating habits. Surgical intervention should be considered in cases that show a significant decrease in the quality of life. Success depends on the malformation’s morphological aspect, the associated pathology, and the skills of the operative team [
74,
75].
Our study has some limitations. First, the small number of cases selected by the chosen protocol does not fully cover the proposed classification. This is based on the embryological evidence and the other articles studied during the elaboration of the manuscript. The classification system will be the basis of future research. Second, the chosen protocol only includes case reports and case series. We chose these inclusion and exclusion criteria in order to be able to benefit from cases where we can identify with certainty the morphological characters followed.