Leonardo Botallo (1530-1587) and his pioneering contributions to traumatology, cardiology and deontology.

Leonardo Botallo (1530-c. 1587) is widely known for the eponymous "foramen Botalli" and "ductus Botalli". The first, most commonly named "foramen ovale", allows blood in the fetal heart to enter the left atrium from the right atrium. The second, named "ductus arteriosus", consists of a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. However, Botallo was a multifaceted figure who studied many aspects of human anatomy and physiology, also making important contributions to clinical and surgical practices. Moreover, as we will see in the last section of this paper, Botallo wrote a book on medical deontology having significant features in relationship to the history of medical ethics. Botallo's multidisciplinary approach is a typical characteristic of Renaissance physicians and scientists, who contributed to making this period a fundamental prelude to the scientific revolution of the 17th century.

The three fetal shunts: A story of wrong eponyms.

The fetal circulatory system bypasses the lungs and liver with three shunts. The foramen ovale allows the transfer of the blood from the right to the left atrium, and the ductus arteriosus permits the transfer of the blood from the pulmonary artery to the aorta. The ductus venosus is the continuation of the umbilical vein, allowing a large part of the oxygenated blood from the placenta to join the supradiaphragmatic inferior vena cava, bypassing the fetal liver and directly connecting the right atrium. These structures are named after the physicians who are thought to have discovered them. The foramen ovale and the ductus arteriosus are called the "foramen Botalli" and the "ductus Botalli," after Leonardo Botallo (1530-c. 1587). The ductus venosus is styled "ductus Arantii" after Giulio Cesare Arantius (1530-1589). However, these eponyms have been incorrectly applied as these structures were, in fact, discovered by others earlier. Indeed, the foramen ovale and the ductus arteriosus were described by Galen of Pergamon centuries earlier (c. 129-210 AD). He understood that these structures were peculiar to the fetal heart and that they undergo closure after birth. The ductus venosus was first described by Andreas Vesalius (1514-1564) 3 years before Arantius. Therefore, the current anatomical nomenclature of the fetal cardiac shunts is historically inappropriate.

Changes in topographical relation between the ductus arteriosus and left subclavian artery in human embryos: a study using serial sagittal sections.

BACKGROUND: At birth, the ductus arteriosus (DA) merges with the aortic arch in the slightly caudal side of the origin of the left subclavian artery (SCA). Since the SCAs (7th segmental arteries) were fixed on the level of the 7th cervical-first thoracic vertebral bodies, the confluence of DA should migrate caudally. We aimed to describe timing and sequence of the topographical change using serial sagittal sections of 36 human embryos and foetuses (CRL 8-64 mm; 5-10 weeks), Those made easy evaluation of the vertebral levels possible in a few section. MATERIALS AND METHODS: The DA or 6th pharyngeal arch artery seemed to slide down in front of the sympathetic nerve trunk along 1.0-1.2 mm from the second cervical vertebral level at 5-6 weeks and, at 6 weeks (CRL 14-17 mm), the DA confluence with aorta reached the 7th cervical level. Because of the highly elongated common carotid artery, the sliding of DA confluence seemed to be much shorter than the cervical vertebrae growing from 1 mm to 2.4 mm. RESULTS: At the final topographical change at 6-7 weeks, the DA confluence further descended to a site 1-vertebral length below the left SCA origin. From 6 to 9 weeks, a distance from the top of the aortic arch to the left SCA origin was almost stable: 0.3-0.5 mm at 6 weeks and 0.4-0.6 mm at 9 weeks. CONCLUSIONS: The heart descent and the caudal extension of the trachea and bronchi, those occurred before the DA sliding, were likely to be a major driving force for the sliding.

Comparative physiology of the ductus arteriosus among vertebrates.

The ductus arteriosus is typically viewed as a mammalian fetal blood vessel providing a right-to-left shunt of right ventricular outflow away from the lungs and to the systemic circuit, that must close at birth. This review provides a wider comparative examination of the ductus arteriosus in lungfish, reptiles, birds, and mammals. The ductus arteriosus evolved with the lung in the ancestors of the lungfish as a connection between the pulmonary arteries and dorsal aorta. During embryonic development, reptiles, birds, and mammals all possess either one or two paired ductus arteriosi that provide a fetal shunt of blood away from the lungs. Differences in the fetal circulatory arrangement are seen between these groups and this influences the importance of the ductus arteriosus as an embryonic shunt. The ductus arteriosus from lungfish and tetrapod vertebrates is an oxygen sensitive blood vessel, with shared conserved pathways involved in oxygen sensing. By expanding studies into more comparative models such as lungfish or developing birds a better understanding of the physiology of the ductus arteriosus can be developed.

Tetralogy of Fallot Surgical Repair: Shunt Configurations, Ductus Arteriosus and the Circle of Willis.

In this study, hemodynamic performance of three novel shunt configurations that are considered for the surgical repair of tetralogy of Fallot (TOF) disease are investigated in detail. Clinical experience suggests that the shunt location, connecting angle, and its diameter can influence the post-operative physiology and the neurodevelopment of the neonatal patient. An experimentally validated second order computational fluid dynamics (CFD) solver and a parametric neonatal diseased great artery model that incorporates the ductus arteriosus (DA) and the full patient-specific circle of Willis (CoW) are employed. Standard truncated resistance CFD boundary conditions are compared with the full cerebral arterial system, which resulted 21, -13, and 37% difference in flow rate at the brachiocephalic, left carotid, and subclavian arteries, respectively. Flow splits at the aortic arch and cerebral arteries are calculated and found to change with shunt configuration significantly for TOF disease. The central direct shunt (direct shunt) has pulmonary flow 5% higher than central oblique shunt (oblique shunt) and 23% higher than modified Blalock Taussig shunt (RPA shunt) while the DA is closed. Maximum wall shear stress (WSS) in the direct shunt configuration is 9 and 60% higher than that of the oblique and RPA shunts, respectively. Patent DA, significantly eliminated the pulmonary flow control function of the shunt repair. These results suggests that, due to the higher flow rates at the pulmonary arteries, the direct shunt, rather than the central oblique, or right pulmonary artery shunts could be preferred by the surgeon. This extended model introduced new hemodynamic performance indices for the cerebral circulation that can correlate with the post-operative neurodevelopment quality of the patient.

Circulatory changes associated with the closure of the ductus arteriosus in hatching emu (Dromaius novaehollandiae).

In developing avian embryos, the right and left ductus arteriosi (DA) allow for a shunt of systemic venous return away from the lungs to the body and chorioallantoic membrane (CAM). Unlike in mammals where the transition from placental respiration to lung respiration is instantaneous, in birds the transition from embryonic CAM respiration to lung respiration can take over 24h. To understand the physiological consequences of this long transition we examined circulatory changes and DA morphological changes during hatching in the emu (Dromaius novaehollandiae), a primitive ratite bird. By tracking microspheres injected into a CAM vein, we observed no change in DA blood flow between the pre-pipped to internally pipped stages. Two hours after external pipping, however, a significant decrease in DA blood flow occurred, evident from a decreased systemic blood flow and subsequent increased lung blood flow. Upon hatching, the right-to-left shunt disappeared. These physiological changes in DA blood flow correspond with a large decrease in DA lumen diameter from the pre-pipped stages to Day 1 hatchlings. Upon hatching, the right-to-left shunt disappeared and at the same time apoptosis of smooth muscle cells began remodeling the DA for permanent closure. After the initial smooth muscle contraction, the lumen disappeared as intimal cushioning formed, the internal elastic lamina degenerated, and numerous cells underwent regulated apoptosis. The DA closed rapidly between the initiation of external pipping and hatching, resulting in circulatory patterns similar to the adult. This response is most likely produced by increased DA constriction in response to increased arterial oxygen levels and the initiation of vessel remodeling.

Reference ranges of ductus arteriosus derived by cardio-spatiotemporal image correlation from 14 to 40 weeks of gestation.

OBJECTIVE: To construct reference ranges of fetal ductus arteriosus (DA) derived by volume datasets of cardio-spatiotemporal image correlation (cardio-STIC). METHODS: Cardio-STIC volume datasets were acquired from low-risk singleton pregnancies with a reliable gestational age from 14 to 40 weeks. In offline analysis with 4D View version 9, fetal DA was measured in the transverse ductal arch view with orthogonal control in the multiplanar view. The reference ranges of the DA and Z-score equation were constructed against gestational weeks and biparietal diameter (BPD) as independent variables. RESULTS: A total of satisfactory 606 volumes were analyzed. The reference ranges for predicting means and SDs of fetal DA were constructed based on the best-fit regression model. Mean DA (mm) was best predicted by linear model as a function of GA (weeks) and BPD (cm) as follows: Predicted DA diameter (cm) = -0.051 + 0.014 × GA (weeks) (r = 0.84) and Predicted DA diameter (cm) = -0.015 + 0.053 × BPD (cm) (r = 0.83). Models for Z-score calculation and centile charts for predicting fetal DA were also provided. CONCLUSION: Reference ranges of the fetal DA and Z-score model are provided. These may serve as a useful tool in the assessment of fetal DA, especially in fetal cardiac anomalies or in monitoring fetuses exposed to maternal indomethacin.

The patent ductus arteriosus in term infants, children, and adults.

During fetal life, the ductus arteriosus is a normal and essential structure that connects the pulmonary artery to the distal aortic arch, permitting right ventricular ejection into the aorta. After birth, with commencement of pulmonary blood flow and a 2-ventricle circulation, a variety of physiological and biochemical signals normally result in complete closure of the ductus. Persistent patency of the ductus arteriosus may impair systemic cardiac output and result in deleterious effects on the cardiovascular system and lungs. Although surgery is still the treatment of choice for most premature infants with patent ductus arteriosus (PDA), transcatheter techniques have largely supplanted surgery for closure of PDA in children and adults. This article is a review of the PDA in term infants, children, and adults, with focus on the clinical manifestations and management.

[Postnatal changes in the ductus arteriosus and brown adipose tissue: a review and an exploratory post-mortem study of lambs]. / Postnatale effecten op de ductus arteriosus botalli enhet bruin vetweefsel. Een literatuuroverzicht en een exploratief post-mortemonderzoek bij lammeren.

After a short review of the literature, postnatal changes in the ductus arteriosus Botalli are described in 52 lambs sampled in 1970 and 1971. Five groups of animals were formed on the basis of findings. (I) All lambs (n = 18) that died of asphyxia or prematurity had open ducti and, in most cases, severe adventitial bleeding (2). Completely anatomically closed ducti were found in I-week-old lambs (n = 9). Lambs that died within about 4 days of birth were grouped as (3) low-birth weight (dysmaturity) (n = 2), (4) normal weight and died after bacterial infection (n = 7), or (5) normal birth weight and died of other causes (n = 6). The dysmature lambs died because of cold and poor suckling. Compared with the lambs with a normal body weight, the dysmature lambs had almost completely closed ducti. Extensive, often circular, haemorrhages at the periphery of the necrotic muscular tissue of the ductal media were found in the dysmature and infected lambs. In these lambs, the brown adipose tissue surrounding the ductus was red-brownish and often depleted of its fat. This fat depletion and haemorrhages were less severe in lambs that died of other causes. The haemorrhages in the media of the ductus arteriosus, which were not found in older lambs, have not been described previously in other species, including humans. These haemorrhages are most likely the result of a short period of ductal relaxation, resulting in the passage of blood through the vasa vasorum and leakage of blood cells from degenerated capillaries at the border of the necrotic muscular tissue. It is hypothesized that the relaxation results from one or a combination of the following: (i) direct heat from heat-producing brown adipose tissue surrounding the ductus (because of cold or infection), (2) infection or inflammatory mediators, and (3) adipose tissue-derived relaxing factors.

History of the ductus arteriosus: 1. Anatomy and spontaneous closure.

Ductus arteriosus and foramen ovale were described by Galen without understanding their functions. His beliefs in soul localization and spiritization within the left ventricle established religious pneumatology which became a theological need in the Middle Ages. Pulmonary transit was recognized by Servetus and Colombo after the Reformation around 1550. This prompted Harvey's full understanding of the fetal circulation. Botallo did not describe the ductus arteriosus, but in 1564 redescribed the foramen ovale, making his way into the nomina anatomica by mistake. Most authors of the 19th and 20th century believed ductal patency to be passive, and postnatal closure to be an active process, explained by mechanical theories. After the discovery of prostaglandins by Bergstrom and Vane, Coceani proved that ductal patency is maintained by the relaxant action of prostaglandins.

Regulation of vascular tone and remodeling of the ductus arteriosus.

The ductus arteriosus (DA), a fetal arterial connection between the main pulmonary artery and the descending aorta, normally closes immediately after birth. The DA is a normal and essential fetal structure. However, it becomes abnormal if it remains patent after birth. Closure of the DA occurs in two phases: functional closure of the lumen within the first hours after birth by smooth muscle constriction, and anatomic occlusion of the lumen over the next several days due to extensive neointimal thickening in human DA. There are several events that promote the DA constriction immediately after birth: (a) an increase in arterial oxygen tension, (b) a dramatic decline in circulating prostaglandinE(2) (PGE(2)), (c) a decrease in blood pressure within the DA lumen, and (d) a decrease in the number of PGE(2) receptors in the DA wall. Anatomical closure of the DA is associated with the formation of intimal thickening, which are characterized by (a) an area of subendothelial deposition of extracellular matrix, (b) the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer, and (c) migration into the subendothelial space of undifferentiated medial smooth muscle cells. In addition to the well-known vasodilatory role of PGE(2), our findings uncovered the role of PGE(2) in anatomical closure of the DA. Chronic PGE(2)-EP4-cyclic AMP (cAMP)-protein kinase A (PKA) signaling during gestation induces vascular remodeling of the DA to promote hyaluronan-mediated intimal thickening and structural closure of the vascular lumen. A novel target of cAMP, Epac, has an acute promoting effect on smooth muscle cell migration without hyaluronan production and thus intimal thickening in the DA. Both EP4-cAMP downstream targets, Epac and PKA, regulate vascular remodeling in the DA.

Morphological changes in the chicken ductus arteriosi during closure at hatching.

The chicken embryo has two functioning ductus arteriosi (DA) during development. These blood vessels connect the pulmonary arteries to the descending aorta providing a right-to-left shunt of blood away from the nonrespiring lungs and to the systemic circuit and chorioallanotic membrane. The DA consists of two distinct tissue types along its length, a muscular proximal portion and an elastic distal portion. During hatching, the DA must close for proper separation of systemic and pulmonary circulation. We examined the morphological changes of the chicken DA before, during, and after hatching. Occlusion of the proximal DA began during external pipping and was complete at hatching. Anatomical remodeling began as early as external pipping with fragmentation of the internal elastic lamina and smooth muscle actin appearing in the neointimal zone. By day 2 posthatch, the proximal DA lumen was fully occluded by endothelial cells and smooth muscle actin positive cells. In contrast, the distal DA was not fully occluded by day 2 posthatch. Increases in Po(2) of the blood serves as the main stimulus for closure of the mammalian DA. The responsiveness of the chicken proximal DA to oxygen increased during hatching, peaking during external pipping. This peak correlated with an increase in blood gas Po(2) and the initial occlusion of the vessel. The distal portion remained unresponsive to oxygen throughout hatching. In conclusion, the chicken DA begins to close during external pipping when arterial Po(2) increases and vessel tone is most sensitive to oxygen.

Morphometric study of the ductus arteriosus during human development.

During prenatal life, the ductus arteriosus connects the left pulmonary artery and the descending aorta. Morphometric features (length, external diameter, volume) of the ductus arteriosus in 131 human fetuses (65 males, 66 females) were studied by means of anatomical, digital and statistical methods. Regression analysis was used to investigate the growth of the ductus arteriosus during gestation. The values of the length of the ductus arteriosus ranged from 3.95 mm for the 15 week gestational group to 12.20 mm for the 34th week of gestation. The length of the ductus arteriosus related to fetal age (x) increased according to the linear function y = -3.0726 + 0.4381x. The mean values of the diameter of the ductus arteriosus ranged from 1.34 to 3.49mm for the 15 and 34 week gestational groups, respectively. The growth of the ductus arteriosus diameter followed in accordance with the linear function y = 0.2072 + 0.0935x. The mean values of the ductus arteriosus volume ranged from 5.08 mm3 for the 15 week group to 117.30 mm3 of the 34 week gestation group. The volume growth increased according to the function y = 0.0007x3.3782. Positive correlation coefficients between arterial parameters and fetal age were statistically significant (P < or = 0.01) and reached the following values: r1 = 0.98 for Length, r2 = 0.90 for diameter and r3 = 0.94 for volume. Despite the increase in absolute diameter, the relative diameter of the ductus arteriosus (ductus arteriosus-to-aortic bulb diameter ratio) decreased from 0.80 to 0.48.

Mechanisms regulating the ductus arteriosus.

A patent ductus arteriosus (PDA) results in increased pulmonary blood flow and redistribution of flow to other organs. Several co-morbidities (i.e., necrotizing enterocolitis, intracranial hemorrhage, pulmonary edema/hemorrhage, bronchopulmonary dysplasia, and retinopathy) are associated with the presence of a PDA, but whether or not a PDA is responsible for their development is still unclear. In this review, comparative physiology between the full term and preterm newborn and the barriers preventing the necessary cascade of events leading to permanent constriction of the PDA are reviewed.

Ductal anatomy: a determinant of successful stenting in hypoplastic left heart syndrome.

Interventional palliation for hypoplastic left heart syndrome (HLHS) could reduce the current morbidity and mortality. Stenting of the arterial duct is the critical interventional step for HLHS. We reviewed our experience with 40 consecutive patients with HLHS referred for stenting of the ductus arterious (DA). Thirty-nine of 40 (97%) infants had suitable anatomy and were successfully stented. The infants were grouped by orientation of the ductus in the frontal plane. Type 1 DA anatomy had a leftward loop at a mean orientation of 18 degrees from the vertical plane. Type 2 ductal anatomy was mesoverted, with a mean orientation of 7.1 degrees from the vertical plane. Type 3 ductal anatomy displayed a rightward axis, with a mean of -4 degrees rightward. Orientation of the DA was significantly related to length of the ductus, number of stents required for complete coverage, and technical and procedural complications. Type 1 DA occurred in 65% of patients, and there was 100% technical success, no mortality, and only an 8% incidence of complications. Type 2 anatomy occurred in 27% of patients and there was 100% success. However, the technical and procedural complications increased to approximately 50%. Type 3 ductal anatomy was seen in only 3 patients, 2 of whom were successfully stented. There was no procedural-related mortality, and all stented patients were weaned from prostaglandin. There were only two late complications (coarctation). We conclude that ductal stenting using self-expanding nitinol stents is successful in more than 95% of infants with HLHS. Patients with HLHS and favorable ductal anatomy should be considered for primary ductal stenting.

The fetal circulation.

Accumulating data on the human fetal circulation shows the similarity to the experimental animal physiology, but with important differences. The human fetus seems to circulate less blood through the placenta, shunt less through the ductus venosus and foramen ovale, but direct more blood through the lungs than the fetal sheep. However, there are substantial individual variations and the pattern changes with gestational age. The normalised umbilical blood flow decreases with gestational age, and, at 28 to 32 weeks, a new level of development seems to be reached. At this stage, the shunting through the ductus venosus and the foramen ovale reaches a minimum, and the flow through the lungs a maximum. The ductus venosus and foramen ovale are functionally closely related and represent an important distributional unit for the venous return. The left portal branch represents a venous watershed, and, similarly, the isthmus aorta an arterial watershed. Thus, the fetal central circulation is a very flexible and adaptive circulatory system. The responses to increased afterload, hypoxaemia and acidaemia in the human fetus are equivalent to those found in animal studies: increased ductus venosus and foramen ovale shunting, increased impedance in the lungs, reduced impedance in the brain, increasingly reversed flow in the aortic isthmus and a more prominent coronary blood flow.

Vasa vasorum hypoperfusion is responsible for medial hypoxia and anatomic remodeling in the newborn lamb ductus arteriosus.

Postnatal constriction of the full-term ductus arteriosus produces hypoxia of the muscle media. This is associated with anatomic remodeling (including smooth muscle death) that prevents subsequent reopening. We used late-gestation fetal and neonatal lambs to determine which factors are responsible for the postnatal hypoxia. Hypoxia [measured by 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide technique] and cell death (measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique) were observed in regions of the constricted ductus wall within 4 h after delivery. Although there was a decrease in ductus luminal flow during the first 6 h after delivery (measured by Doppler transducer), the amount of oxygen delivered to the ductus lumen (3070 +/- 1880 micromol O2 x min(-1) x g(-1)) far exceeded the amount of oxygen consumed by the constricted ductus (0.052 +/- 0.021 micromol O2 x min(-1) x g(-1), measured in vitro). Postnatal constriction increased the effective oxygen diffusion distance across the ductus wall to >3x the limit that can be tolerated for normal tissue homeostasis. This was owing to both an increase in the thickness of the ductus (fetus, 1.12 +/- 0.20 mm; newborn, 1.60 +/- 0.17 mm; p < 0.01) and a marked reduction in vasa vasorum flow (fetus, 0.99 +/- 0.44 mL x min(-1) x g(-1); newborn, 0.21 +/- 0.08 mL x min(-1) x g(-1); p < 0.01). These findings suggest that hypoxic cell death in the full-term ductus is caused primarily by changes in vasa vasorum flow and muscle media thickness and can occur before luminal flow has been eliminated. We speculate that in contrast with the full-term ductus, the preterm ductus is much less likely to develop the degree of hypoxia needed for vessel remodeling inasmuch as it only is capable of increasing its oxygen diffusion distance to 1.3x the maximally tolerated limit.

Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon.

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.