Ventricular Topology in Visceral Isomerism:Novel Associations with Cardiovascular Phenotypes and Survival

Introduction

Methods

Results

Plate 1. Right Visceral Isomerism vs Left Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 1. Right Visceral Isomerism vs Left Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 2. D-Hand vs L-Hand Topology. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 2. D-Hand vs L-Hand Topology. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 3. D-hand vs L-hand Topology in Right Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 3. D-hand vs L-hand Topology in Right Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 4. D-hand vs L-hand Topology in Left Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Plate 4. D-hand vs L-hand Topology in Left Visceral Isomerism. Note: Statistically significant P-value results were marked with a red star right next to the significant variable in the list of variables to the left side of the graph.

Congenital Disorders of Excitation and Conduction (Plates 1-4 and Table 5 in ODS)

With regard to inferior and superior p-wave axis, it was noted that among RVI patients there was a statistically significant higher rate of inferior p-wave axis (88%) compared to LVI patients (50%) (p-value 0.0001), reflecting higher prevalence of sinus node absence or dysfunction, and higher prevalence of ectopic atrial pacemakers in patients with LVI.

Combined with the data on ventricular topology, we did not find a statistically significant difference in the presence of inferior p-wave axis between RVI hearts with D-hand (93%) and L-hand (81%) ventricles (p-value 0.28). The same holds true for patients with LVI, where an inferior p-wave axis was found in 47% of D-hand ventricles and 57% of L-hand ventricles (p-value 0.58).

With regard to left and right p-wave axis, we noted that among RVI patients there was an almost equal distribution of left (50%) and right (45%) p-wave axis. However, in the LVI group, left p-wave axis was predominant (left (77%), right (33%), (p-value 0.02)), reflecting a higher prevalence of a left-sided cardiac apex in patients with LVI compared to patients with RVI.

RVI hearts with ventricular D-hand topology showed a statistically significant higher rate of left axis (61%) compared to right (36%), reflecting the higher tendency for a left-sided cardiac apex in this particular group (see above). RVI hearts with ventricular L-hand topology showed higher rates of right axis (58%), reflecting in turn the high rates of a right-sided cardiac apex in this setting.

LVI hearts with ventricular L-hand topology showed a statistically significantly higher rate of right axis (63%) compared to left axis (37%), while LVI with ventricular D-hand topology showed a higher prevalence of left axis (78%) compared to right (21%) (p-value 0.0001). The data correlates with high prevalence of a right-sided cardiac apex in L-hand group and a left-sided cardiac apex in the D-hand group.

There were no statistically significant differences in prevalence of atrial arrhythmias in all groups:

(1)

RVI (23%) vs. LVI (23%), (p-value 0.17);

(2)

ventricular D-hand topology (23%) vs. L –hand topology (22 %) (p-value 0.42);

(3)

ventricular D-hand topology (27%) in RVI vs. L-hand topology in RVI (18%) (p-value 0.31);

(4)

ventricular D-hand topology (21%) in LVI vs. L-hand topology in LVI (27%) (p-value 0.71).

When comparing rates of conduction defects whether congenital or acquired, the prevalence in RVI group was almost zero, apart from one patient who had an iatrogenic atrioventricular block requiring insertion of a pacemaker.

And when comparing the total conduction defects (AV block and junctional combined), there was only statistically significant differences when comparing RVI and LVI groups with LVI group having higher conduction defects (35%) compared to RVI group (13%), (P-value 0.003). The high percentage conduction defects in LVI group was mostly sinus node dysfunction (32%) followed by atrioventricular block (3%) while he percentage of sinus node dysfunction in RVI group was 12% and all of them had intermittent junctional rhythm only (p-value 0.003).

The looping pattern showed no much difference between D-hand and L-hand ventricles with near incidence of conduction defects (D-hand: 25%; and L-hand: 28%; p-value 0.21). The D-hand in RVI showed 6 patients with intermittent junctional rhythm compared to 3 patients in L-hand with RVI (p-value 0.33). The L-hand in LVI showed a higher percentage of congenital AV block (2 patients) with no similar incidence in D-hand with LVI. The numbers for junctional rhythm were comparable between the D-hand and L-hand ventricles for LVI (30% and 37%, respectively), with similar distribution for intermittent and permanent junctional rhythms (p-value 0.18).

• Mortality and Long-Term Survival

With regard to mortality, our data showed a statistically significant difference between the RVI and LVI sub-groups (Plate 1 and Table 6 in ODS): in the RVI sub-group, more than half of the patients died or were missed (55 %), while in the LVI sub-group only a fourth of the patients died or were missed (24 %); (p-value 0.0001).

When we analyzed the relation between ventricular topology and mortality, the following findings were made:

Among the whole study population, there was no statistically significant difference in mortality between the patients with ventricular D-hand (38 %) and L-hand (33 %) topology; (p-value 0.53). (Plate 2 and Table 6 in ODS).

The same holds true for the RVI sub-group (D-hand (55 %), and L-hand (55 %); p-value 1). (Plate 3 and Table 6 in ODS).

Among the LVI sub-group, however, there was a significantly lower mortality in patients with ventricular L-hand topology (10 %) compared to the patients with D-hand topology (71 %), (p-value 0.03). (Plate 4 and Table 6 in ODS).

With regard to long-term survival (follow-up of at 5, 10 and 15 years) as shown in Figure 1 and Table 7 in ODS we found that RVI patients had a significantly worse outcome over the years (55%, 43%, and 32 %) at 5, 10, 15 years compared to LVI patients (84 %, 76% and 72 %) at the same period, (p-value 0.0001),

Figure 1. Kaplan-Meier survival curves illustrating the differences in mortality among different groups over a 15-year follow-up period. Censoring events are marked with crosses on the respective curves.

Figure 1. Kaplan-Meier survival curves illustrating the differences in mortality among different groups over a 15-year follow-up period. Censoring events are marked with crosses on the respective curves.

When we analyzed the relation between ventricular topology and long-term survival, the following findings were made.

Among the whole study population, there was no statistically significant difference in long-term survival between the patient with ventricular D-hand (71 %, 60 %, and 53 %) and L-hand topology (73 %, 66%, and 46 %), (p-value 0.49).

The same holds true for the RVI sub-group (D-hand: 53%, 41 %, and 33 %; L-hand: 53 %, 40%, and 32 %; p-value 0.77).

In the LVI sub-group, however, there was a statistically significant difference in long term survival between the patients with D-hand and L-hand ventricles. Patients with ventricular L-hand topology showed a much better long-term survival (97 %, 97 % and 97 %) than patients with ventricular D-hand topology (79 %, 69 % and 64 %) (p-value 0.014).

Discussion

Statistical Distribution Patterns of Ventricular D-Hand and L-Hand Topology

With regard to the distribution pattern of ventricular topology, we found that, among the whole cohort of patients with visceral isomerism syndrome, there was a statistically asymmetric distribution pattern characterized by a bias toward D-hand topology (67% vs. 33%). When we segregated our data with regard to the two subsets of the syndrome, we found that D-hand as well as L-hand topology occurred in both subsets. There was, however, a striking difference between the RVI and LVI groups. While the LVI patients showed a statistically significant bias toward the presence of ventricular D-hand topology (74% vs. 26%), the RVI subset showed an almost equal distribution of D-hand and L-hand topologies (57% vs. 43%). These patterns do not fit to the currently popular idea that ventricular looping is mainly driven by chiral forces intrinsic to the ventricular segment of the embryonic heart. If we assume that the spin (chirality) of these forces is determined by the molecular L-R patterning of the embryonic heart, we should expect that the visceral isomerism syndrome displays a binary distribution pattern in which ventricular L-hand topology should tend to occur only in the RVI subset and D-hand topology should tend to occur only in the LVI subset (see Figure 2).

Figure 2. This scheme depicts the expected scenarios of ventricular looping if this process would be driven by intrinsic chiral forces whose spin (D-handed (red arrows), L-handed (green arrows)) is defined by molecular L-R patterning of the embryonic heart. A: Normal development. Ventricular looping is dominated by the D-handed forces within the left half of the heart tube. B: RVI. Molecular right isomerism induces L-handed forces in both halves of the heart tube. C: LVI. Molecular left isomerism induces D-handed forces in both halves of the heart tube.

Figure 2. This scheme depicts the expected scenarios of ventricular looping if this process would be driven by intrinsic chiral forces whose spin (D-handed (red arrows), L-handed (green arrows)) is defined by molecular L-R patterning of the embryonic heart. A: Normal development. Ventricular looping is dominated by the D-handed forces within the left half of the heart tube. B: RVI. Molecular right isomerism induces L-handed forces in both halves of the heart tube. C: LVI. Molecular left isomerism induces D-handed forces in both halves of the heart tube.

On the other hand, however, our data also do not seem to fit completely to the alternative hypothesis, which says that the lateral twist of the bending embryonic heart tube mainly evolves in consequence of mechanical loads from the pericardial wall, which constrains ventral bending of the growing heart tube. According to this hypothesis, asymmetric expression of molecular determinants of L-R identities is not responsible for the chiral deformation of the ventricular heart segment but only for generating a bias toward development of one of the two alternative phenotypes (ventricular D-hand or L-hand topology). The bias inducing mechanism is attributed to morphological and/or functional asymmetries located at the venous and arterial poles of the linear heart tube [31,32,33,34]. In this scenario, both, the RVI as well as LVI subsets are expected to suffer from a lack of ventricular topology bias during the embryonic period of cardiogenesis and, therefore, should display a tendency for statistically symmetric distribution of ventricular D-hand and L-hand topologies; a pattern that may be regarded as reflection of the syndrome-specific tendency for visceral symmetry at the level of the ventricular heart segment. In our patients such a tendency for symmetry was present only in the RVI subset (57 % vs. 43 %) while the LVI subset displayed a statistically significant bias toward D-hand topology (74 % vs. 26 %). In view of the ambiguous situation two questions arise: (1), do our present data correspond to previously published data; and (2), how can we explain the observed deviation from a statistically symmetric distribution pattern?

Information on ventricular topology is provided only in a limited number of studies on patients with cardiac malformations in the setting of visceral isomerism syndrome. Table 1 presents the distribution patterns of ventricular D-hand and L-hand topology found in these studies. At first sight, an analysis of these data does not seem to disclose a common pattern. Some studies present statistically almost symmetric distributions of ventricular D-hand and L-hand topologies among RVI as well as LVI patients [13,38,39]. Others present distribution patterns similar to our data [8], and the largest group of studies presents asymmetric distribution patterns that are found in RVI as well as LVI cases and are characterized by a moderate (~ 60:40) bias [40,41,42,43,44]. Interestingly, this bias was toward the presence of D-hand topology in all but a single study [45]. Pooling of the data from all studies shown in Tab. 1 discloses that the bias toward ventricular D-hand topology is stronger in the LVI subset (63.8 %) than in the RVI subset (55.4 %) of the visceral isomerism syndrome. This finding principally corresponds to our data although we observed a much stronger bias toward D-hand topology among our LVI patients (74% vs. 26%).

Table 1. Ventricular topology in patients with cardiac malformations in the setting of visceral isomerism syndrome (data from previous studies).

Table 1. Ventricular topology in patients with cardiac malformations in the setting of visceral isomerism syndrome (data from previous studies).

	RVI				LVI
Study	Case no.	D-hand	L-hand	Undetermined	Case no.	D-hand	L-hand	Undetermined
Stanger et al. [45]	23 *	34.8 % (8)	65.2 % (15)		17 *	70.6 % (12)	29.4 % (5)
Carvalho et al. [38]	13	54 % (7)	46 % (6)		12	50 % (6)	50 % (6)
Vairo et al. [39]					28	53 % (15)	47 % (13)
Francalanci et al. [40]	33 *	60.6 % (20)	39.4 % (13)
Ho et al. [41]	10 *	60 % (6)	40 % (4)		20 *	65 % (13)	10 % (2)	25 % (5)
Uemura et al. [8]	125 *	54 % (68)	42 % (52)	4 % (5)	58 *	79 % (46)	16 % (9)	5 % (3)
Smith et al. [11]	10 *	20 % (2)	20 % (2)	60 % (6)	25 *	60 % (15)	32 % (8)	8 % (2)
Yildirim et al. [66]	43	53.5 % (23)	18.6 % (8)	27.9 % (12)	88	59.1 % (52)	22.7 % (20)	18.2 % (16)
Loomba et al. [13]	37 *	50 %	42 %	8 %	12 *	47 %	53 %
Tremblay et al. [42]	131 *	61 % (80)	36 % (47)	3 % (4)	56 *	66 % (37)	34 % (19)
Kiram et al. [43]	184	57.6 % (106)	41.9 % (77)	0.5 % (1)	118	66.1 % (78)	33.1 % (39)	0.8 % (1)
Oreto et al. [44]	43	60.5 % (26)	39.5 % (17)		35	57 % (20)	43 % (15)
Pooled data	652	55.4 % (361)	39.9 % (260)	4.7 % (31)	469	63.8 % (299)	30.5 % (143)	5.7 % (27)

* postmortem analysis.

How can we explain the above-described deviations from statistically symmetric distribution patterns? At first, we should note that our data as well as the data from the majority of the above-mentioned studies come from postnatal patients. The distribution patterns of ventricular D-hand and L-hand topology among a cohort of postnatal patients with visceral isomerism do not only depend on the syndrome-specific allocation of ventricular topology at embryonic stages of development, but are additionally influenced by the natural history of affected patients during the fetal and perinatal periods of development. Previous data from postmortem hearts obtained from human patients with visceral isomerism syndrome (fetal and postnatal) have provided evidence for a strong association between the presence of ventricular L-hand topology and anomalies in the atrio-ventricular conduction axes among the RVI as well as LVI subset [11]. Moreover, analyses of the outcome of prenatally diagnosed cases of visceral isomerism have shown that the intrauterine mortality of affected fetuses is high in the presence of hydrops caused by congenital atrio-ventricular block [46,47]. In view of these findings, and in view of the fact that congenital heart block preferentially affects LVI patients [47], it is tempting to speculate that the above-described deviations from a statistically symmetric distribution of ventricular D-hand and L-hand topologies are caused by a higher rate of arrhythmia-related fetal death in isomerism patients with ventricular L-hand topology as compared to patients with ventricular D-hand topology, especially in the subset of LVI. Due to the high rate of terminations of pregnancy subsequent to a prenatal diagnosis of visceral isomerism [47]. and due to technical difficulties in assessing ventricular topologies of fetal hearts in utero, it is unlikely that this hypothesis can be tested in the near future by documenting the natural history of prenatally diagnosed cases. Analysis of postnatal data for the presence of statistically significant associations between ventricular topology and the occurrence of life-threatening cardiovascular disorders (arrhythmias, malformations), as well as patient’s survival might be an alternative way to test the hypothesis. Our present data, however, did not uncover any statistically significant association between ventricular topology and the presence of life-threatening congenital arrhythmias or complex cardiovascular malformations. Moreover, we made the unexpected and somewhat puzzling finding that, among our LVI patients, the rate of long-term survival was higher in patients with ventricular L-hand topology compared to those with D-hand topology (Figure 1). We have no sound explanation for this finding. Since previous studies had never looked for possible associations between ventricular topology and mortality/survival, future studies are needed to clarify the situation.

A second possible cause for the above-described deviations from statistically symmetric distribution patterns might be attributed to the composition of study populations. Data from animal models and human patients have shown that the clinical diagnosis visceral isomerism syndrome or heterotaxy characterizes a genetically very heterogeneous entity [48]. Studies on animal models, furthermore, have shown that, with regard to ventricular topology, we principally can distinguish between two different types of genetic animal models for visceral isomerism; (1) those in which the presence of atrial isomerism is regularly associated with randomization of ventricular topology; and (2) those in which atrial isomerism is associated with ventricular D-hand topology, only. While the first type encompasses the vast majority of animal models for visceral isomerism (e.g [49,50,51]), the second type encompasses only a relatively small group, which includes mutations/defects in lefty1 [52], sonic hedgehog [53,54], and Pitx2 [55]. At the present time, it is unknown why these mutants retain the normal bias toward development of ventricular D-hand topology. In view of this observation, however, we should be aware of the possibility that the statistical distribution pattern of ventricular D-hand and L-hand topology found among cohorts of human patients with visceral isomerism might depend on the proportion of patients carrying mutations in one of the three above-mentioned genes.

Cardiovascular Anomalies in the Setting of Visceral Isomerism, Their Distribution Among RVI and LVI Subsets, and Associations with Ventricular D-Hand and L-Hand Topology

It is well known that the visceral isomerism syndrome is usually associated with complex cardiac malformations and that the two subsets of the syndrome (RVI, LVI) differ from each other with regard to the pattern of associated cardiovascular disorders and with regard to clinical prognosis. [7,42]. The patterns found in the present study correspond to these well-known patterns (Plate 1). When we looked for statistically significant associations between the type of ventricular topology and cardiovascular disorders, we found that, among the whole cohort as well as among the RVI and LVI subsets, there were no significant differences between the two variants of ventricular topology with regard to the prevalence of cardiovascular disorders that have strong influence on the prognosis of patients with visceral isomerism (Plates 2-4). There were a few anatomical features of minor prognostic importance, however, that displayed a statistically significant association with either the ventricular D-hand or L-hand topology among the whole cohort as well as among the RVI and LVI subsets. These features are: (1) position of the cardiac apex; (2) direction of the p-wave axis; and (3) aortic arch sidedness (Plates 2-4). In the following paragraphs, these three features will be discussed with regard to the embryology of the anatomical situs of the cardiovascular system.

Position of the cardiac apex. In contemporary as well as older articles on the embryology of visceral asymmetries, the normally left-sided position (levo-position) of the apex of the human heart is frequently described as a feature that reflects the looping morphogenesis of the embryonic heart. According to this view, we should expect that, in the setting of visceral isomerism syndrome, ventricular D-hand topology should be regularly associated with levo-position of the cardiac apex, while ventricular L-hand topology should display a regular association with dextro-position of the cardiac apex. Our present data indeed disclosed statistically significant associations between levo-position of the apex and ventricular D-hand topology (64-83%), and dextro-position and ventricular L-hand topology (70-77%). We should emphasize, however, that our data, which correspond to previous data (see Figure 1 in Ticho et al [15]), do not indicate a regular association. We therefore have to conclude that the direction of embryonic heart looping seems to play a strong but not exclusive role in positioning of the cardiac apex.

Direction of p-wave axis. With regard to this feature, we found that the presence of left p-wave axis was associated with D-hand topology (58-63%), while the presence of right p-wave axis was associated with L-hand topology (63-78%). It is well known that the direction of p-wave axis corresponds to the position of the cardiac apex [56]. Our data therefore seem to reflect the positioning of the cardiac apex.

Aortic arch sidedness. The normal arrangement of the human aortic arch and its major arterial branches is characterized mainly by the presence of a single, left-sided aortic arch and represents a well-known example of visceral asymmetry near to the center of our cardiovascular system. It results from asymmetric remodeling of the originally bilateral symmetric system of paired pharyngeal arch arteries during the embryonic period of prenatal development [57,58,59]. In view of this fact, it is tempting to speculate that, in the setting of visceral isomerism, the aortic arch system should display a tendency for bilateral symmetric arrangements, characterized by a high prevalence of double aortic arch. Surprisingly, however, such arrangements do not characterize the visceral isomerism syndrome of humans [60]. as well as animal models [61]. Instead, it is stated that the syndrome is characterized by randomization of aortic arch sidedness [61]. The presence of a right aortic arch is a rare finding among humans without malformations. Its frequency is estimated at 0.1% in a normal population [62]. Normal L-R patterning of the human aortic arch system thus is characterized by a strong bias toward the presence of a left aortic arch. This situation resembles the L-R patterning of the ventricular segment of the human heart where spontaneous reversal of topology is estimated at 0.01% [21]. Our present data show that a right aortic arch is a very frequent finding among patients with visceral isomerism. This finding corresponds to previous data [62,63,64]. With regard to statistical distribution patterns of left and right aortic arches, we found that the whole cohort of our isomerism patients as well as the two subsets of the syndrome, all displayed almost symmetric distribution patterns, that showed only small or moderate but statistically non significant bias toward the occurrence of a left aortic arch (whole cohort: 56.25% vs. 43.75%; RVI: 49% vs. 51%; LVI: 61% vs. 39%). This finding seems to confirm the above-mentioned statement that visceral isomerism is characterized by randomization of aortic arch sidedness [61]. We should note, however, that our data do not correspond to all previously published data. As shown in Table 2, there is a great variability among the data from previous studies, which may be explained in part by low case numbers. Pooling of these data discloses distribution patterns that are closer to randomization but show a small (RVI) to moderate (LVI) bias toward the presence of a left aortic arch.

Table 2. Aortic arch sidedness among patients with cardiac malformations in the setting of visceral isomerism syndrome (data from previous studies).

Table 2. Aortic arch sidedness among patients with cardiac malformations in the setting of visceral isomerism syndrome (data from previous studies).

	RVI					LVI
Study	Case no.	Left arch	Right arch	Double arch	Undet.	Case no.	Left arch	Right arch	Double arch	Undet.
Ho et al. [41]	10 *	50 % (5)	50 % (5)			20 *	75 % (15)	25 % (5)
Francalanci et al. [40]	33 *	60.6 % (20)	39.4 % (13)
Smith et al. [11]	10 *	90 % (9)	10 % (1)			25 *	88 % (22)	12 % (3)
Loomba et al. [13]	37 *	70 % (26)	30 % (11)			12 *	95 % (11)	5 % (1)
Tremblay et al. [42]	131 *	63 % (77)	37 % (46)		8	57 *	75 % (41)	25 % (15)		1
Kiram et al. [43]	184	46.7 % (86)	53.3 % (98)			118	60 % (71)	40 % (47)
Oreto et al. [44]	43	70 % (30)	30 % (13)			35	51 % (18)	49 % (17)
Pooled data	448	56.5 % (253)	41.7 % (187)		1.8 % (8)	267	66.6 % (178)	33 % (88)		0.4 % (1)

This table shows data from studies that presented data on ventricular topology and aortic arch sidedness. * postmortem analysis.

It appears that, in the setting of visceral isomerism, the sidedness of the definitive aortic arch seems to represent a binary anatomical variable that can exist either in the form of a right-sided or left-sided aortic arch. A bilaterally symmetric third form (double aortic arch) virtually does not occur in the syndrome. Thus, the syndrome-specific tendency for bilaterally symmetric arrangement of inner organs usually does not appear in the aortic arch system of individual patients. The present data as well as previously published data, however, suggest that the syndrome-specific tendency for visceral symmetry becomes apparent at the population level where it appears as a tendency for statistically symmetric (randomized) distribution of right and left-sided aortic arches. This situation resembles the above-described situation found at the ventricular heart segment of patients with visceral isomerism. In view of the fact that, in the setting of visceral isomerism, ventricular topology and aortic arch sidedness have previously been described as randomized features, one might wonder that our study is the first to check patients’ data for the presence of statistically significant links between the two anatomical variables. Thus, our data are the first to show that, in the setting of visceral isomerism, there is a statistically significant association between ventricular D-hand topology and the presence of a left aortic arch (whole cohort: 69%; RVI: 61%; LVI: 73%), while ventricular L-hand topology is associated with right aortic arch (whole cohort: 70 %; RVI: 67%; LVI: 73%).

It is the question as to whether these associations might reflect ontogenetic relationships. In the setting of visceral isomerism, the emergence of a unilateral aortic arch can hardly be ascribed to molecular determinants of body sidedness since these determinants should be expressed in bilaterally symmetric fashions. It is therefore tempting to speculate that asymmetric remodeling of the embryonic pharyngeal arch arteries is mainly controlled by other factors such as hemodynamic load. Data from animal models for visceral isomerism and flow simulation studies, indeed, support the hypothesis that asymmetric remodeling of the pharyngeal arch arterial system is mainly driven by asymmetric routing of blood flow in consequence of chiral morphogenesis of the ventricular outflow tract (Yashihiro et al. 2007; Kowalski et al. 2012) [61,65]. We therefore think that the associations between ventricular topology and aortic arch sidedness, found in the present study, reflect the dependence of pharyngeal arch arterial remodeling on ventricular looping.

Conclusions

References

1. Ramsdell AF. Left–right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left–right axis determination. Developmental Biology. 2005;288:1–20. [CrossRef]
2. Nakamura T, Hamada H. Left-right patterning: conserved and divergent mechanisms. Development. 2012;139:3257–3262. [CrossRef]
3. Männer J. The functional significance of cardiac looping: comparative embryology, anatomy, and physiology of the looped design of vertebrate hearts. Journal of Cardiovascular Development and Disease. 2024;11:252. [CrossRef]
4. Ivemark BI. Implications of agenesis of the spleen on the pathogenesis of cono-truncus anomalies in childhood. Acta Paediatrica. 1955;44(Suppl. 104):7–113. [CrossRef]
5. Moller JH, Nakib A, Anderson RC, Edwards JE. Congenital cardiac disease associated with polysplenia. A developmental complex of bilateral „left-sidedness“. Circulation. 1967;36:789–799. [CrossRef]
6. Stanger P, Benassi RC, Korns ME, Jue KL, Edwards JE. Diagrammatic portrayal of variations in cardiac structure. Reference to transposition, dextrocardia and the concept of four normal hearts. Circulation. 1968;37(Suppl. 4):1–16. [CrossRef]
7. Bartram U, Wirbelauer J, Speer CP. Heterotaxy syndrome–asplenia and polysplenia as indicators of visceral malposition and complex congenital heart disease. Neonatology. 2005;88:278–290. [CrossRef]
8. Uemura H, Ho SY, Devine WA, Kilpatrick LL, Anderson RH. Atrial appendages and venoatrial connections in hearts with patients with visceral heterotaxy. The Annals of Thoracic Surgery. 1995;60:561–569. [CrossRef]
9. De Tommasi S, Daliento L, Ho SY, Macartney FJ, Anderson RH. Analysis of atrioventricular junction, ventricular mass, and ventriculoarterial junction in 43 specimens with atrial isomerism. British Heart Journal. 1981;45:236–247. [CrossRef]
10. Ho SY, Seo JW, Brown NA, Cook AC, Fagg NL, Anderson RH. Morphology of the sinus node in human and mouse hearts with isomerism of the atrial appendages. British Heart Journal. 1995;74:437–442. [CrossRef]
11. Smith A, Ho SY, Anderson RH, Connell MG, Arnold R, Wilkinson JL, Cook AC. The diverse cardiac morphology seen in hearts with isomerism of the atrial appendages with reference to the disposition of the specialised conduction system. Cardiology in the Young. 2006;16:437–454. [CrossRef]
12. Anderson RH, Brown NA, Meno C, Spicer DE. The importance of being isomeric. Clinical Anatomy. 2015;28:477–486. [CrossRef]
13. Loomba RS, Ahmed MM, Spicer DE, Backer CL, Anderson RH. Manifestations of bodily isomerism. Cardiovascular Pathology. 2016;25:173–180. [CrossRef]
14. Anderson RH, Spicer DE, Loomba RS. Is an appreciation of isomerism the key to unlocking the mysteries of cardiac findings in heterotaxy? Journal of Cardiovascular Development and Disease. 2018;5:11. [CrossRef]
15. Ticho BS, Goldstein AM, Van Praagh R. Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. The American Journal of Cardiology. 2000;85:729–734. [CrossRef]
16. Goldstein AM, Ticho BS, Fishman MC. Patterning the heart’s left-right axis: From zebrafish to man. Developmental Genetics. 1998;22:278–287.
17. Lander A, King T, Brown NA. Left–right development: mammalian phenotypes and conceptual models. Seminars in Cell & Developmental Biology. 1998;9:35–41. [CrossRef]
18. Anderson RH, Webb S, Brown NA. Defective lateralisation in children with congenitally malformed hearts. Cardiology in the Young. 1998;8:512–531. [CrossRef]
19. Männer J. The anatomy of cardiac looping: a step towards the understanding of the morphogenesis of several forms of congenital malformations. Clinical Anatomy. 2009;22:21–35. [CrossRef]
20. Moorman AFM, Soufan AT, Hagoort J, De Boer PAJ, Christoffels VM. Development of the building plan of the heart. Annals of the New York Academy of Sciences. 2004;1015:171–181. [CrossRef]
21. Palmer AR. Symmetry breaking and the evolution of development. Science. 2004;306:828–833. [CrossRef]
22. Inaki M, Liu J, Matsuno K. Cell chirality: its origin and roles in left–right asymmetric development. Philosophical Transactions of the Royal Society B: Biological Sciences. 2016;371(1710):20150403. [CrossRef]
23. Rahman T, Zhang H, Fan J, Wan LQ. Cell chirality in cardiovascular development and disease. APL Bioengineering. 2020;4:031503. [CrossRef]
24. Ekman G. Experimentelle Beiträge zur Herzentwicklung der Amphibien. Wilhelm Roux’s Archives of Developmental Biology. 1925;106:320–352. [CrossRef]
25. Copenhaver WM. Experiments on the development of the heart of Amblystoma punctatum. Journal of Experimental Zoology. 1926;43:321–371. [CrossRef]
26. Goerttler K. Die Bedeutung der ventrolateralen Mesodermbezirke für die Herzanlage der Amphibienkeime. Anatomischer Anzeiger. 1928;66(Suppl.):132–139.
27. DeHaan R. Cardia bifida and the development of pacemaker function in the early chick heart. Developmental Biology. 1959;1:586–602. [CrossRef]
28. Zwirner R, Kuhlo B. Die prospektive Potenz der rechten und der linken Herzanlage (ein experimenteller Beitrag zur Asymmetrie des Herzens). Wilhelm Roux’s Archives of Developmental Biology. 1964;155:511–524. [CrossRef]
29. Nadal-Ginard B, Paz Garcia M. The morphologic expression of each cardiac primordium in the chick embryo. Journal of Embryology and Experimental Morphology. 1972;28:141–152. [CrossRef]
30. Weiss PA. Entwicklungsphysiologie der Tiere. Steinkopff; 1930. [CrossRef]
31. Taber, LA. Taber LA. Biophysical mechanisms of cardiac looping. International Journal of Developmental Biology. 2006;50:323–332. [CrossRef]
32. Taber LA, Voronov DA, Ramasubramanian A. The role of mechanical forces in the torsional component of cardiac looping. Annals of the New York Academy of Sciences. 2010;1188:103–110. [CrossRef]
33. Shi Y, Yao J, Young JM, Fee JA, Perucchio R, Taber LA. Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry. Frontiers in Physiology. 2014;5:297. [CrossRef]
34. Bayraktar M, Männer J. Cardiac looping may be driven by compressive loads resulting from unequal growth of the heart and pericardial cavity. Observations on a physical simulation model. Frontiers in Physiology. 2014;5:112. [CrossRef]
35. Huhta JC, Smallhorn JF, MacCartney FJ. Two dimensional echocardiographic diagnosis of situs. British Heart Journal. 1982;48:97–108. [CrossRef]
36. Jacobs JP, Anderson RH, Weinberg PM, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Beland MJ, Colan SD et al. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. Cardiology in the Young. 2007;17(S4):1–28. [CrossRef]
37. Al-Zahrani RS, Alharbi SH, Tuwaijri RM, Alzomaili BT, Althubaiti A, Yelbuz TM. Transposition of the great arteries: A laterality defect in the group of heterotaxy syndromes or an outflow tract malformation? Annals of Pediatric Cardiology. 2018;11:237–249. [CrossRef]
38. Carvalho JS, Rigby ML, Shinebourne EA, Anderson RH. Cross sectional echocardiography for recognition of ventricular topology in atrioventricular septal defect. Heart. 1989;61:285–288. [CrossRef]
39. Vairo U, Marino B, Parretti di Iulio D, Guccione P, Carotti A, Formigari R et al. Ventricular-infundibular morphology in visceral heterotaxia with left isomerism. An echocardiographic-angiocardiographic study. Giornale Italiano di Cardiologia. 1991;21:969–974.
40. Francalanci P, Marino B, Boldrini R, Abella R, Iorio F, Bosman C. Morphology of the atrioventricular valve in asplenia syndrome: a peculiar type of atrioventricular canal defect. Cardiovascular Pathology. 1996;5:145–151. [CrossRef]
41. Ho SY, Cook A, Anderson RH, Allan LD, Fagg N. Isomerism of the atrial appendages in the fetus. Pediatric Pathology. 1991;11:589–608. [CrossRef]
42. Tremblay C, Loomba RS, Frommelt PC, Perrin D, Spicer DE, Backer C, Anderson RH. Segregating bodily isomerism or heterotaxy: potential echocardiographic correlations of morphological findings. Cardiology in the Young. 2017;27:1470–1480. [CrossRef]
43. Kiram VS, Choudhary S, Shaik A, Gadabanahalli K, Raj V, Bhat V. Spectrum of cardiac anomalies associated with heterotaxy: a single-center study of a large series based on computed tomography. Pediatric Cardiology. 2020;41:1414–1424. [CrossRef]
44. Oreto L, Mandraffino G, Ciliberti P, Santangelo TP, Romeo P, Celona A, Gitto P, Galetti L, Iorio FS, Di Pino A et al. Classifying anomalies in right and left isomerism: concordant and discordant patterns. Congenital Heart Disease. 2023;18:97–111. [CrossRef]
45. Stanger P, Abraham MR, Edwards JE. Cardiac malpositions. An overview based on sixty-five necropsy specimens. Circulation. 1977;56:159–172.
46. Berg C, Geipel A, Kamil D, Knüppel M, Breuer J, Krapp M, Baschat A, Germer U, Hansmann M, Gembruch U et al. The syndrome of left atrial isomerism. Sonographic findings and outcome in prenatally diagnosed cases. Journal of Ultrasound in Medicine. 2005;24:921–931. [CrossRef]
47. Buca DIP, Khalil A, Rizzo G, Familiari A, Di Giovanni S, Liberati M, Murgano D, Ricciardulli A, Fanfani F, Scambia G et al. Outcome of prenatally diagnosed fetal heterotaxy: systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology. 2018;51:323–330. [CrossRef]
48. Deng H, Xia H, Deng S. Genetic basis of human left-right asymmetry disorders. Expert Reviews in Molecular Medicine. 2014;16:e19. [CrossRef]
49. Icardo JM, Sanchez de Vega MJ. Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation. 1991;84:2547–2558. [CrossRef]
50. Weininger WJ, Lopes Floro K, Bennett MB, Withington SL, Preis JI, Barbera JP, Mohun TJ, Dunwoodie SL. Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development. Development. 2005;132:1337–1348. [CrossRef]
51. Bamforth SD, Braganca J, Farthing CR, Schneider JE, Broadbent C, Michell AC, Clarke K, Neubauer S, Norris D, Brown N et al. Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nature Genetics. 2004;11:1189–1196. [CrossRef]
52. Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, Ohishi S, Noji S, Kondho H, Hamada H. Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell. 1998;94:287–297. [CrossRef]
53. Tsukui T, Capdevila J, Tamura K, Ruiz-Lozano P, Rodriguez-Esteban C, Yonei-Tamura S, Magallon J, Chandraratna RA, Chien K, Blumberg B et al. Multiple left-right asymmetry defects in Shh (-/-) mice unveil a convergence of the Shh and retinoic acid pathways in the control of Lefty-1. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:11356–11381.
54. Hildreth V, Webb S, Chaudry B, Peat JD, Phillips HM, Brown N, Anderson RH, Henderson DJ. Left cardiac isomerism in the sonic hedgehog null mouse. Journal of Anatomy. 2009;214:894–904. [CrossRef]
55. Lin CR, Kioussi C, O’Cannell S, Briata P, Szeto D, Liu F, Izpisua-Belmonte JC, Rosenfeld MG. Pitx2 regulated lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature. 1999;401:279–282. [CrossRef]
56. Green JM, Chiaramida AJ. 12-lead EKG Confidence: A Step-by-step Guide. Springer Publishing Company; 2014. 115.
57. Congdon ED. Transformation of the aortic arch system during development of the human embryo. Contributions to Embryology. 1922;68:49–110.
58. Rana MS, Sizarov A, Christoffels VM, Moorman AFM. Development of the human aortic arch system captured in an interactive three-dimensional reference model. American Journal of Medical Genetics Part A. 2014;164:1372–1383. [CrossRef]
59. Anderson RH, Bamforth SD. Morphogenesis of the mammalian aortic arch arteries. Frontiers in Cell and Developmental Biology. 2022;10:892900. [CrossRef]
60. Loomba RS, Hlavacek AM, Spicer DE, Anderson RH. Isomerism or heterotaxy: which term leads to better understanding. Cardiology in the Young. 2015;25:1037–1043. [CrossRef]
61. Yashihiro K, Shiratori H, Hamada H. Haemodynamics determined by a genetic program govern asymmetric development of the aortic arch. Nature. 2007;450:285–288. [CrossRef]
62. Hastreiter AR, D’Cruz IA, Cantez T. Right-sided aortic arch. Part I: Occurrence of right aortic arch in various types of congenital heart disease. British Heart Journal. 1966;28:722–725. [CrossRef]
63. Rose V, Izukawa T, Moes CAF. Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. British Heart Journal. 1975;37:840–852. [CrossRef]
64. Peoples WM, Moller JH, Edwards JE. Polysplenia: a review of 146 cases. Pediatric Cardiology. 1983;4:129–137. [CrossRef]
65. Kowalski WJ, Teslovich NC, Dur O, Keller BB, Pekkan K. Computational hemodynamics optimization predicts dominant aortic arch selection is driven by embryonic outflow tract orientation in the chick embryo. Biomechanics and Modeling in Mechanobiology. 2012;11:1057–1073. [CrossRef]
66. Yildirim SV, Tokel K, Varan B, Aslamaci S, Ekici E. Clinical investigations over 13 years to establish the nature of the cardiac defects in patients having abnormalities of lateralization. Cardiology in the Young. 2007;17:275–282. [CrossRef]