Teratology

CHAPTER 19 Teratology



Fred Sinowatz



HISTORY OF TERATOLOGY


Teratology is the study of abnormal development. The idea that extrinsic influences ranging from ‘evil spirits’ to diet may influence the development of human and animal embryos has been held since Antiquity, but it became more precise in the nineteenth century with Etienne Geoffroy de Saint Hilaire, who studied in great detail several prenatal anomalies like cyclocephalia, anencephaly, and twin monsters and also coined the very term ‘teratology’. In the last century two sets of findings strongly influenced the establishment of teratology as a scientific discipline strongly connected to embryology. The first set concerned the deleterious effects of hyper- and hypovitaminosis A on mouse and pig embryos. The second, and more dramatic, set related to the effects of thalidomide, a sedative used to prevent morning sickness during early pregnancy in humans, and which resulted in devastatingly severe limb defects in numerous newborns in Europe during the late 1950s and early 1960s. Since then, the number of known and suspected teratogens has grown tremendously. Recently, the possibility that cloning by somatic cell nuclear transfer can cause severe malformations has caused concern, with developmental defects being attributed to incomplete reprogramming of the somatic cell genome by the oocyte cytoplasm (see Chapter 21).



GENERAL PRINCIPLES


Contrary to the situation in humans, reliable data on the occurrence of congenital defects in domestic animals are not readily available. The frequency of congenital malformations varies with species, breed, geographical locations and many other factors. Various studies indicate that approximately 1.5% to 6% of all live-born domestic mammals show at least one recognizable congenital malformation. Such malformations are comparatively infrequent in cats but occur to an upper limit of 3–4% in sheep, cattle and horses and in up to 6% of newborn dogs and pigs. They range from complex associations of gross anatomical abnormalities to enzyme defects caused by single nucleotide substitution detectable only with molecular diagnostic tools. Traditionally, it has been structural defects that have been emphasized in veterinary embryology textbooks, but it should be kept in mind that congenital malformations really encompass a continuum ranging from purely biochemical abnormalities to gross anatomical defects and include derangements of function, metabolism and behaviour.


The genesis of congenital malformations is best regarded as an interaction between the genetic constitution of an embryo and the environment in which it develops. The basic instructions for embryonic development are encoded in the genes. As the genetic instructions unfold, the developing structures interact with environmental influences that either are either compatible with normal development or interfere with it; penetration (the degree of manifestation) of an abnormal gene, or of the components of a genetically multifactorial cascade, can be markedly affected by environmental conditions.



CRITICAL PERIODS OF SUSCEPTIBILITY TO ABNORMAL DEVELOPMENT


As we have seen, the developing embryo consists of groups of cells that are growing, differentiating, and undergoing morphogenesis at different rates and over different time periods, but in a strictly controlled sequence of events. Therefore, one of the most important principles of teratology is that the susceptibility to an agent causing malformation – a teratogen – varies with the developmental stage of the embryo at the time of exposure. From many studies the following conclusions can be drawn:


• Insults to the embryo during the first 3 weeks of gestation (during which the basic body plan is established) are unlikely to result in defective development, because they either kill the embryo or can be compensated by regulatory mechanisms in the early embryo. Agents that disrupt the morula or blastocyst stage, or disturb the normal embryo-maternal communication and interfere with normal apposition of the conceptus to the uterine mucosa, usually induce early embryonic mortality.

• The period of maximal susceptibility begins when organogenesis is initiated at three weeks and extends in most organ systems up to the eighth week. Although most major organs are established during this period, exceptions are the very complex organs like the brain and major sense organs, which show prolonged periods of high susceptibility, and the reproductive organs, which develop comparatively late.

• After eight weeks of gestation, major structural anomalies are unlikely to occur. At this time, most organs are well-established.

This picture of susceptible periods is rather simplified; it must be remembered that although exposure to a teratogen or some other harmful influence might be at an early stage of development, the expression of the defects it causes may be seen only at a later stage of embryogenesis. Often, an induced lesion in one system can cause secondary malformation in others. This occurs, for instance, during the development of the heart or the central nervous system.


Not all teratogens act in the same developmental periods. Some are harmful at an early stage of development but not later in pregnancy. Thalidomide is a well-known example, causing malformations of the limbs in humans during a very narrow window of development (considered to be between 34 and 50 days after the beginning of the mother’s last menstrual period). Other teratogens affect only later developmental stages; the antibiotic tetracyline, for example, which stains teeth and other bony structures, can only do so after these hard tissues have been formed in the fetus.


Although there are many examples of isolated structural or biochemical defects, it is quite common to find multiple abnormalities in the same individual. This phenomenon can result from a single teratogen acting on the primordia of several organs during their susceptible periods. Another possibility is that a single defective gene affects the structure and metabolism of multiple developing organs.



CAUSES OF MALFORMATIONS



Significance of genotype


Since normal development is controlled by an interaction between the genome of an embryo and its environment, susceptibility to a teratogen depends upon the genotype of the embryo and the manner in which it interacts with adverse environmental factors. This principle is best documented by the fact that some materials that are teratogenic in one species do not cause malformation in other species. A well-known example of this is that cortisone, which when given to mice at a particular developmental stage readily produces cleft palate, does not affect other laboratory species. Furthermore, differences in susceptibility to teratogens have been found even in different strains of mice.


Genetically based malformations result from abnormalities of chromosomal division or mutations of genes. Abnormal genes may either be the direct cause of an anomaly, or may induce the anomaly indirectly by affecting the susceptibility of the embryo to an environmental insult. Thus, the predisposition to an insult may be inherited.



Abnormal chromosome numbers


Quantitative changes in chromosomal numbers result in polyploidy or aneuploidy. In polyploidy, the chromosomal number is more than twice the haploid number of chromosomes of a given species. Most polyploid embryos are aborted early in pregnancy. Potential causes of polyploidy are fertilization of an egg by more than one sperm (polyspermy) or lack of separation of a polar body during meiosis of the oocyte. Embryos may also display mixoploidy, where a group of normal diploid cells is mixed with another portion of polyploid cells. This situation probably results from the lack of cytokinesis during initial mitoses. Interestingly, up to 25% of normal blastocysts recovered from cows are mixoploid and have a low percentage of polyploid cells, most of which become sequestered in the trophectoderm later in development. The incidence of mixoploidy is increased in embryos produced in vitro or by somatic cell nuclear transfer (see Chapter 21).


Numerical errors in the number of a particular chromosome result in aneuploidy. This is defined as a total number of chromosomes other than the usual haploid set for a given species. Monosomy is the lack of one member of a chromosome pair. In trisomy, a triplet instead of a normal chromosome pair occurs. Both events are typically the result of nondisjunction during meiosis. A number of conditions resulting from monosomy and trisomy are listed in Table 19-1. In most cases, embryos with monosomy of the autosomes and sex chromosomes cannot survive. However, in man as well as in domestic animals, individuals with monosomy of the X-chromosome (XO genotype) are viable. In humans, this condition is called Turner’s syndrome, characterized by a female phenotype with sterile ovaries.



Table 19-1: Effects of abnormal karyotypes due to sex chromosome non-disjunction

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Abnormalities in chromosome structure


Abnormalities in chromosome structure can cause malformations of development. Radiation or certain chemical teratogens can cause chromosome breakages and deletions (loss of parts of chromosomes). If a piece of a broken chromosome does not contain a kinetochore, it is lost because it cannot move towards a spindle pole during anaphase. Deletion results in the loss of genetic information. Other common types of structural defects of chromosomes are reciprocal translocation, inversion and centric fusion. Reciprocal translocation results when two non-homologous chromosomes each break into two segments and then exchange segments. Animals with a reciprocal translocation in their genome are usually of normal phenotype but their fertility is significantly reduced. Centric fusion occurs when two acrocentric chromosomes merge to form a metacentric chromosome. Cattle with centric fusion have normal phenotypes but show an increased frequency of monosomy and trisomy in their offspring.


Many genetic mutations are expressed as functional or morphological abnormalities. These can affect recessive or dominant genes and for some of these conditions the molecular and biochemical lesions have been identified. Many of these aberrations are extensively described in textbooks of veterinary genetics and some representative examples will be discussed later in this chapter.



Abnormalities caused by assisted reproductive technologies


Abnormally large offspring, with a body weight increased by 10–50%, are more frequently born following assisted reproductive technologies (see Chapter 21). In cattle and sheep this large offspring syndrome (LOS) is often associated with neonatal respiratory distress and perinatal death. The aetiology of LOS is not fully elucidated but it has been proposed that some growth factors in the sera used for embryo culture, co-culture of the embryos with feeder cells, an asynchronous uterine environment, or other unknown factors in assisted reproductive technologies may be involved.


Many aspects of LOS in farm animals, especially the somatic overgrowth, are reminiscent of Beckwith-Wiedemann syndrome (BWS) in humans. New data suggest that BWS is induced by loss of imprinting and consequent over-expression of the gene encoding insulin-like growth factor 2 (IGF2). In sheep, a similar mechanism has been elucidated in relation to LOS, a region in intron 2 of the IGF2 receptor (IFG2R) gene displaying differences in DNA methylation, the mechanism by which the expression of imprinted genes is controlled. This gene is imprinted in the mouse, possibly variably imprinted in humans, and appears to be imprinted in the sheep as well. It has recently been demonstrated that sheep fetuses, developing from embryos cultured under conditions promoting LOS, display loss of maternal IGF2R gene methylation and decreased expression of this receptor. This epigenetic aberration is likely to be causally involved in LOS and demonstrates that even subtle manipulations of gametes and embryos may induce epigenetic aberrations that manifest themselves later during embryonic development.


Most studies on LOS have been performed in cattle where the reported abnormalities include increased rates of early embryonic mortality, production of large fetuses and calves (newborn calves weighing up to 80 kg), disproportionate and abnormal organ growth, musculoskeletal deformities, abnormalities of placental vasculature, and hydroallantois. Recently, comparable abnormalities have been reported in mice, sheep and pigs.


The extreme heterogeneity of LOS phenotypes has made it difficult to define the underlying causes and has led to the proposal by Farin et al. (2006) that the term ‘abnormal offspring syndrome (AOS)’ would more accurately describe the range of abnormal developmental changes following transfer of in vitro produced and cloned embryos in cattle and other species. These authors also proposed the following functional classification system of developmental outcomes resulting from transfer of such embryos:


• Type I AOS: Abnormal development and death of the embryo or early conceptus prior to completion of organogenesis (approximately Day 42 of gestation in cattle).

• Type II AOS: Abnormal development of placenta, fetal membranes, and fetus; fetus dies between completion of organ differentiation and full term (Day 42 to 280 of gestation in cattle).

• Type III AOS: A full term fetus and/or placenta with severe developmental abnormalities and no evidence of compensatory response by the fetus. Parturition is normal (eutocia) or difficult (dystocia). The calves are severely compromised with altered clinical, haematological, or biochemical parameters. Death occurs around the time of parturition or during the neonatal period.

• Type IV AOS: A full term fetus and/or placenta with moderate abnormalities; however, the feto-placental unit compensates and adapts to the compromising genetic or physiological insults and survives. Parturition is normal or difficult. The calves may be normal or abnormal in size for their breed, and they may have clinical, haematological, or biochemical abnormalities.

These abnormal AOS phenotypes resulting from in vitro production of embryos and cloning are stochastic in occurrence. It should also be mentioned that recent reports have documented that cloned animals may display normal fetal development, birth and post-natal development. It is likely that improvement of the technologies employed will alleviate some of the impacts imposed on the gametes and embryos and result in fewer abnormalities.



Environmental factors



Mechanical factors


Several common anomalies, such as clubfoot, congenital hip dislocations, and certain deformations of the skull have been attributed to mechanical factors that impose an abnormal intrauterine pressure on the fetus. This phenomenon is often related to a reduced amount of fluid in the amniotic cavity or to uterine malformations in the mother. Amniotic bands may form as the result of tears to the extra-embryonic membranes during pregnancy. If they constrict digits or extremities of the fetus, they may cause intrauterine amputations.



Physical factors


Ionizing radiation is a potent teratogen in all species. The response depends on the dose and the stage of development at which the embryo is exposed to the radiation. As ionizing radiation can cause breaks of DNA strands and is also known to cause mutations, exposure of pregnant animals to radiation should be avoided, although the dose in a diagnostic X-ray examination it usually so small that the risk is minimal. Strong ionizing radiation can result in a variety of congenital defects including microcephaly, cleft palate, and other skeletal malformations. Defects of the central nervous system are also prominent in irradiated embryos.



Chemical factors


Any chemical substance that has the potential to alter cellular function or which is cytotoxic has the potential of being teratogenic. The mechanisms that lead to teratogenesis vary. For example, some drugs can inhibit specific enzyme systems (e.g. carbonic anhydrase), interfere with DNA metabolism, or disturb particular metabolic activities. Retinoic acid, for instance, acts as a potent teratogen when taken orally. This compound produces a wide spectrum of defects, most of which are related to derivatives of the cranial neural crest. These involve facial structures, the heart, and the thymus. As described in Chapter 8, neural crest cells from rhombomeres are instrumental in patterning many structures of the face and neck and contribute to the outflow tract of the heart. Retinoic acid affects the expression of Hox genes in the cranial and pharyngeal regions causing alterations of the anterior rhombomeres and of the neural crest cells derived from them.


It has been shown that at defined exposure levels and at critical stages of development, several therapeutic drugs can also be potentially teratogenic (Table 19-2). Special caution should be taken when prescribing cytotoxic drugs such as antimitotic or anthelminthic agents to pregnant animals. For some of these drugs, the teratogenic effects on the developing embryo are well understood. However, for many substances it is still not clear in which species and at what concentrations they might be teratogenic. For instance, the classic teratogen thalidomide is highly teratogenic in humans, rabbits, and some primates, but not in the commonly used laboratory rodents. The use of some antibiotics during pregnancy has been associated with congenital defects: streptomycin in high dose can result in inner ear deafness; tetracycline can cross the placental barrier and cause a yellowish discolouration of teeth (and, in high doses, interfere with enamel formation) when given late in pregnancy.



Table 19-2: Teratogenic drugs

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Many poisonous plants containing toxic or teratogenic compounds have been implicated in congenital defects in herbivorous animals. Some of these compounds are listed in Table 19-3. The malformations produced vary widely and include skeletal deformities, limb defects, cyclopia and cleft palate. As with other agents, there are distinct times during development when the embryo or fetus is particularly susceptible to certain plant teratogens. A well-known example is the effect of Veratrum californicum which induces congenital cyclopia if consumed by ewes at around Day 14 of pregnancy.



Table 19-3: Common teratogenic plants

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Infectious agents


Most infectious diseases that cause birth defects are viral. The pathogenicity of a virus, the stage of gestation at which infection occurs, and the immunological competence of the fetus determines the outcome of in utero viral infections. A summary of infectious virus diseases that can cause birth defects in domestic animals is given in Table 19-4. During early development, the zona pellucida is protective against viral infections, but when the blastocyst hatches from the zona pellucida, the embryo becomes vulnerable to attack by viruses. Many viral infections are toxic and/or lethal to the embryo. Later, the placental barrier prevents viral infections to some degree but many viruses can cross the placental barrier. Therefore maternal viral infections at critical stages of development can be a serious cause of malformations. Infection of pregnant sheep, cattle, and goats with Akabane virus causes teratogenic defects (e.g. arthrogryposis; hydranencephaly) that are closely related to fetal age at time of infection.


Table 19-4: Common teratogenic viruses



































































Virus Species affected Effects
Akabane virus Cattle, sheep, goat Brain defects (hydranencephaly, porencephaly), limb defects (arthrogryposis)
Bluetongue virus Sheep, cattle, goats Brain, spinal cord, limb defects
Border disease virus Sheep, goats Wide range of embryonic and fetal changes, skeletal growth retardation, cerebellar dysplasia
Bovine rhinotracheitis Cattle Embryotoxic
Bovine viral diarrhoea Cattle Embryonic death; abnormalities of the central nervous system and ocular abnormalities
Classical swine fever Pigs Malformation of the central nervous system (cerebellar and spinal hypoplasia)
Equine rhinopneumonitis Horses Embryotoxic
Equine encephalitis Horses Limb defect
Feline panleukopaenia Cats Cerebellar defects, retinal dysplasia
Herpesvirus 2 Dogs Eye, brain defects
Japanese encephalitis Pigs, sometimes horses Hydrocephalus, cerebellar hypoplasia, hypomyelinogenesis
Porcine herpesvirus 1 Pigs Abortion, stillborn or mummified piglets
Porcine parvovirus Pigs Abortion, stillborn or mummified piglets
Rift valley fever virus Sheep, cattle, goat Arthrogryposis, hydranencephaly, cerebellar hypoplasia, microcephaly
Rubella Monkey, rabbit Heart, eye, brain and skeletal defects


CLASSIFICATION OF MALFORMATIONS


The major types of developmental disturbances found in domestic animals include:



Agenesis or aplasia


This is a developmental failure of an organ or part of an organ to form. It results in the absence of the involved structure. Absence of the lens (aphakia) or a kidney (renal agenesis) can be due to absent or abnormal inductive tissue interactions during development.



Hypoplasia and hyperplasia


The normal formation of organs requires a precise control of cellular proliferation. If cellular proliferation in developing organs is reduced, the organ becomes too small (hypoplastic). Increased proliferation results in hyperplasia, where organs become too large. Even relatively minor growth changes can cause severe problems in complex regions of the body such as the face.



Failure to fuse or close


Fusion is a basic morphogenic process involved in the formation of many structures (Fig. 19-1). Therefore, failure of completion of a fusion process is one of the more important types of developmental defects. Examples are cleft palate, defects in the diaphragm, and various septal defects in the heart. A classic case is the failure of tube formation in spina bifida anomalies, in which fusion of the neural tube is incomplete.


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Fig. 19-1: Failure of a fusion process is one of the more important types of developmental defects. In the example here, the body wall of the thorax and abdomen of a puppy has failed to fuse.


Courtesy Sinowatz and Rüsse (2007).



Absence of normal cell death


Genetically or epigenetically controlled cell death in the form of apoptosis is an important mechanism in forming certain structures of the body. For instance, syndactyly (webbed digits) occurs when normal cell death fails to occur in the interdigital areas.



Disturbances in tissue resorption


Some structures present in the early embryo must be resorbed for normal development. Examples include the resorption of the oro-pharyngeal membrane and the cloacal membrane that cover the future oral and anal openings. Anal atresia is a common anomaly in piglets.



Failure of migration


Failure of migration can occur at the level of cells or entire organs. An important example is the migration of cells of the neural crest. Disturbances in migration cause malformations in any of the structures in which the participation of neural crest cells is important, for example the thymus, outflow tracts of the heart, and the adrenal medulla. At the organ level, the kidneys normally ascend from their origin in the pelvic region to the upper part of the abdominal cavity. If migration fails, the result is pelvic kidneys. Other examples are ectopic cordis, in which the heart is located outside of the thoracic cavity, and cryptorchidism, in which the testes are not in the scrotum.



Developmental arrest


Some malformations are characterized by the persistence of structures in a state that was normal at an earlier state of development. An example is the persistence of a thyroglossal duct in which persisting epithelial cells mark the path of the thyroid gland as it migrates from the base of the tongue to its normal position.



Duplication and reversal of asymmetry (Figs 19-2, 19-3, 19-4, 19-5)


Under normal circumstances, both members of a twin pair are completely separated. Sometimes the separation is not complete and the twins remain conjoined to various degrees and at almost any site of their bodies. In the extreme, one member of the pair is more or less normal whereas the other has a much smaller body, often consisting of just the torso and limbs (parasitic twins).


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Fig. 19-2: These twin pigs are conjoined at the thorax and head, resulting in a cephalothoracopagus.


Courtesy Sinowatz and Rüsse (2007).


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Fig. 19-3: Cephalopagus of a bull calf.


Courtesy Sinowatz and Rüsse (2007).


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Fig. 19-4: The brain of the calf shown in Fig. 19-3 shows a doubling of the hemispheres but only one brain stem.


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Fig. 19-5: Dicephalus in a goat.


Courtesy Sinowatz and Rüsse (2007).



ORGAN MALFORMATIONS


The following descriptions of major malformations in the organ systems should be read in conjunction with former chapters that describe their normal development.



CONGENITAL MALFORMATIONS OF THE CARDIOVASCULAR SYSTEM



Congenital heart malformations (Fig. 19-6)


Heart defects represent the most common class of congenital malformation. Cardiac malformations are more frequently encountered in dogs and cattle than in horses and cats. Clinically, heart malformations are typically classified as cyanotic or acyanotic, depending on whether they are associated with cyanosis in postnatal life. In animals with acyanotic malformations the body receives sufficient oxygenated blood to maintain life-sustaining levels of activity. In cyanotic malformation the body receives insufficient oxygenated haemoglobin in the peripheral capillary bed. Cyanosis is readily diagnosed by the purplish to bluish tinge in tissues with a dense superficial capillary circulation, most easily seen in the oral mucosa and gums.


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Fig. 19-6: Schematic representation of cardiac malformations (modified according to Noden and De Lanhunta, 1985).


A: Atrial septal defect (ASD). The blood is shunted from left to right, because of the higher pressure in the left atrium. The right heart becomes overloaded and overworked from the additional volume of blood it receives. The result is dilatation and hypertrophy of the right atrium and ventricle.


B: Ventricular septal defect (VSD) is characterized by the presence of a small opening at the dorsal part of the interventricular septum. The physiological consequences are determined by the size and the relative resistance in the systemic and pulmonary vascular beds.


C: Pulmonary stenosis (PS) is one of the most common cardiac defects in dogs. It can be present as a single defect or associated with other heart defects. Obstruction of the right ventricular outflow tract cause increased resistance to ejection, leading to right ventricular hypertrophy and septal flattening.


D: Aortic stenosis, obstruction of the left ventricular outflow (LVOT) is caused by a proliferative thickening encircling the aortic outlet immediately below the aortic valves. It results in a ventricular overload, which causes hypertrophy of the left ventricle.


E: Tetralogy of Fallot. It is characterized by a large ventricular septal defect, an aorta that overrides the left and right ventricles, obstruction of the right ventricular outflow (pulmonary stenosis) and right ventricular hypertrophy.


Courtesy Sinowatz and Rüsse (2007).



Ectopia cordis


Ectopia cordis, the condition in which the heart does not attain its expected position in the thorax, is most frequently reported in cattle. Often, the heart remains in the neck region (ectopia cordis cervicalis). The initial position of the cardiogenic area is anterior to the oro-pharyngeal membrane and the neural plate. With the anteroposterior folding of the embryo proper in conjunction with the closure of the neural tube and growth of the brain vesicles, the cardiogenic field and the developing heart with the future pericardial cavity is brought to a cervical location. Later, further migration into the thorax is accomplished. A delay in the onset of cardiac descent can trap the heart at, for example, a cervical location. Occasionally, the paired sternal bars that form the sternum do not fuse and the heart may be located outside the thorax. This condition is called ectopia cordis thoracis.



Dextrocardia


Dextrocardia is a malformation in which the heart lies more to the right side of the thorax than to the left. This condition is caused early in development, when the heart tube loops to the left instead of the right. Dextrocardia may be associated with situs inversus, a complete reversal of asymmetry in all organs. In this anomaly the chambers normally on the left and right are reversed in position and the ductus arteriosus, aortic arches and pulmonary veins form on the right. The condition can be compatible with normal life. In other cases sidedness is random and only some organs show a reversed position. This condition is called heterotaxy and is associated with an increased incidence of other malformations, especially heart defects.



Acyanotic heart malformations


Acyanotic malformations are the most commonly encountered congenital heart anomalies, especially in dogs, and include the following.



Obstruction of the left ventricular outflow (aortic stenosis)


Obstruction of the left ventricular outflow tract (LVOT) is one of the most common congenital heart defects and is usually caused by a proliferative thickening that forms a fibromuscular ring around the aortic outlet immediately below the aortic valve. It is quite frequently detected in large breed of dogs (e.g. Golden Retrievers, Rottweilers, Boxers, German Shepherds and Samoyeds). Although supravalvular and valvular forms of aortic stenosis have been recognised, fibromuscular subaortic stenosis, causing a fixed form, is the most common form in the dog. In cats aortic stenosis is uncommon but valvular and supravalvular forms of LVOT have been reported and the incidence of subaortic stenosis is somewhat higher in Siamese cats.


Three different grades of severity of LVOT obstruction have been described:


• Grade 1: The lesion consists of small, raised nodules of thickened endocardium of the interventricular septum below the aortic valve.

• Grade 2: The lesion forms a narrow ridge of thickened fibrous endocardium that partially encircled the LVOT below the aortic valve.

• Grade 3: The lesion forms a fibrous band, ridge or collar completely encircling the LVOT just below the aortic valve.

The most severe effects are generally found in dogs older than six months but pups of just a few weeks of age may be affected by severe forms of stenosis.


LVOT obstruction results in a ventricular pressure overload which requires higher systolic pressure to maintain adequate stroke volume. The ventricle hypertrophies, increasing the demand for myocardial blood flow. Aortic pressures are normal but left ventricular luminal pressures are higher than normal, so that the coronary driving pressure may be inadequate and coronary flow may sometimes be in a reversed direction during systole. Papillary muscles and subendocardial regions are the areas most commonly affected by syncope. Although cardiac output is normal at rest, the fixed obstruction makes it difficult to increase the stroke volume in response to the exercise as would occur normally. This lowers exercise tolerance and may induce syncope. Eventually a poststenotic dilation develops in the ascending aorta distal to the valve. Clinically signs vary considerably, from none at all to characteristic left heart failure (with characteristic pulmonary congestion and oedema, panting, coughing, and dyspnoea). Until recently, surgery on this malformation has not been successful and most patients are managed medically.



Pulmonary stenosis


Uncomplicated pulmonary stenosis (i.e. without other heart anomalies) is one of the most common cardiac defects in dogs of breeds predisposed to the condition (English Bulldogs, Mastiffs, Fox Terriers, Samoyeds, miniature Schnauzers, Cocker Spaniels, and West Highland White Terriers are particularly susceptible). An hereditary form of pulmonary valve dysplasia has been found in the Beagle (with a polygenetic mode of transmission) and Boykin Spaniel.


Pulmonary stenosis consists of a narrowing of the pulmonary outflow and can occur at several possible sites. Although subvalvular and supravalvular forms of pulmonary stenosis have been reported, the most common form of the right ventricular obstruction in dogs is pulmonary valve dysplasia which can be present as a single defect or associated with other heart defects. A pulmonary artery atresia represents the extreme form of obstruction of the right ventricular tract. The nature of the obstruction can be diagnosed by echocardiography. When valvular fusion exists, the semilunar cusps are fused towards the tips of the leaflet, resulting in doming of the valves. When hypoplastic type of pulmonary stenosis is present, the valve appears thickened and immobile and the annulus may be narrow and hypoplastic. The main haemodynamic effects of pulmonary stenosis can be visualized as concentric right ventricular hypertrophy, paradoxical septal motion, and reduced size of the left atrium and left ventricle in moderate to severe pulmonary stenosis. Dilatation of the main pulmonary artery can be seen distally to the obstruction, close to the bifurcation. Spectral Doppler echocardiography of pulmonary stenosis will record increased peak pulmonary artery velocity (>1.6 m/s) and often prominent pulmonary insufficiency. A Doppler gradient across the stenosis of <50 mm Hg is considered as mild pulmonary stenosis. Gradients between 50 and 100 mm Hg are moderate in severity and higher gradients are associated with severe pulmonary stenosis.


Obstruction of the right ventricular outflow tract causes increased resistance to ejection and a proportional increase in ventricular systole pressure leading to right ventricular hypertrophy, leftward septal flattening, and a systolic gradient across the pulmonary valve. Clinical signs may not occur in puppies, but the onset of right heart failure are usually seen between 6 months and 3 years of age. Typical symptoms of right heart failure include fatigue, weakness, dyspnoea, and venous congestion.



Ventricular septal defects


Ventricular septal defects are characterized by the presence of a small opening at the dorsal part of the interventricular septum. Depending on the location, ventricular septal defects are classified as: (a) membranous/perimembranous (the most common type in dogs), (b) outflow (infundibular/supracristal), (c) inflow (atrioventricular canal), and (d) muscular (trabecular). They are caused by a deficient growth of one or more of the septa that normally close the interventricular foramen (ventricular septum, conu-truncal cushions). Ventricular septal defects can appear as isolated lesions or in association with other heart defects such as pulmonary stenosis, pulmonary atresia, truncus arteriosus, and double-outlet right ventricle. Some defects can predispose the animal to prolapse of the aortic valve into the defect.


The physiologic consequences of a ventricular septal defect depend on the size of the defect and the relative resistance in the systemic and pulmonary vascular beds. If the defect is small (’restrictive’ ventricular septal defect), there is little or no functional disturbance, since pulmonary blood flow is increased only minimally. In fact, many bovine hearts have small ventricular septal defects. In contrast, if the defect is large (‘non restrictive’ ventricular septal defect), right ventricular dilatation and hypertrophy occur. Often, a ventricular septal defect is accompanied by other cardiac malformations, some of which probably arise secondarily and can produce cyanotic signs. Ventricular septal defects have been reported in all domestic species. Among dogs it is more common in English Bulldogs, Keeshonds (in which a genetic basis has been documented), English Springer Spaniels, and Beagles.



Atrial septal defects


Atrial septal defects, characterized by an opening in the interatrial septum, have been described in all domestic species. In dogs, they are more common in Boxers and Samoyeds. Atrial septal defects occur when the foramen ovale of the septum secundum overlies one (or more) openings in the septum primum. Functionally the blood is shunted from left to right, because of the higher pressure in the left atrium. The right heart becomes overloaded and overworked from the additional volume of blood it receives. The result is dilatation and hypertrophy of the right atrium and ventricle. The left heart also frequently undergoes hypertrophy.



Dysplasia of the atrioventricular valves


Dysplasia of the atrioventricular valves is caused by an abnormal development of the atrioventricular cushions that lead to the formation of valve cusps that are too short to fully close the atrioventricular orifice. The condition has been reported in all domestic species. A wide spectrum of lesions has been identified in dogs and cats with atrioventricular valve malformations, including anomalies in valve leaflets, chordae tendineae and/or papillary muscles. Dysplasia of the atrioventricular valves may appear as an isolated lesion or in association with others defects such as subvalvular aortic stenosis (SAS), ventricular septal defects, or atrial septal defects. Cats, and the following dog breeds show a predisposition to mitral dysplasia: Great Danes, German Shepherds, Bull Terriers, Golden Retrievers, Newfoundlands, Dalmatians, and Mastiffs. Tricuspid dysplasia has also been reported in cats. Regurgitation of blood occurs upon systole. This condition is often called left atrioventricular valve insufficiency and usually leads to left heart failure.



Cyanotic heart malformations


Two deviations from normal cardiac blood flow characterize most cyanotic heart malformations: a venoatrial shunt, that allows the blood flow between the right and left sides of the heart; and an impediment to pulmonary tract outflow. Two conditions that include these deviations are the Tetralogy of Fallot and the Eisenmenger syndrome.



Tetralogy of Fallot


Tetralogy of Fallot is the most common cyanotic congenital heart defect in domestic animals and is characterized by the following four lesions: a large ventricular septal defect, an aorta that overrides the left and right ventricles, obstruction of the right ventricular outflow tract (pulmonary stenosis), and right ventricular hypertrophy. These anomalies are produced by a failure of the conu-truncal cushions and septum to align properly. Pulmonary stenosis causes resistance to flow from the right ventricle, which consequently dilates and hypertrophies. This is aggravated by the left-to-right flow of left ventricular blood and results in right ventricular hypertrophy, the fourth lesion characteristic of the Tetralogy of Fallot. As a result of the right ventricular outflow tract obstruction and elevated right ventricular systolic pressure, desaturated blood is shunted through the ventricular septal defect to mix with blood entering the left ventricle. Chronic hypoxaemia may result in polycythaemia by increasing renin production and release of erythropoietin. Signs of this heart defect usually occur in young animals. Even limited exercise often causes marked cyanosis. Other symptoms are fatigue, poor growth, dyspnoea on exercise and occasionally episodic syncope.



Eisenmenger syndrome


This malformation is similar to the Tetralogy of Fallot except that no pulmonary stenosis is found. The primary defects consist of a slight dextro-aorta and a large interventricular septal defect. This condition arises from hypoplasia of the proximal portions of the cushions of the bulbus cordis during heart development. Eisenmenger syndrome is characterized by an elevated pulmonary vascular resistance and right-to-left shunting of blood through a systemic-to-pulmonary circulation connection such as a patent ductus arteriosus, ventricular septal defects, atrial septal defects, and aortico-pulmonary septal defects. This additional source of blood induces the right ventricle to dilate and hypertrophy.


With substantial left-to-right shunting, the exposure of the pulmonary vasculature to increased blood flow as well as increased pressure often results in pulmonary vascular obstructive disease, leading to increased pulmonary vascular resistance. As the pulmonary vascular resistance approaches or exceeds systemic resistance, the shunt is reversed and cyanosis appears. The right ventricle becomes hypertrophied because it must eject against a high pulmonary vascular resistance. Perfusion of the kidneys with hypoxaemic blood leads to secondary polycythemia.



Transposition of great vessels


Reversal of systemic and pulmonary outflows is a rare event. On rare occasions the conu-truncal cushions fail to spiral as they divide the outflow tract into two channels. This causes the fourth aortic arches to connect with the right ventricles and the sixth aortic arches with the left ventricle. This results in two totally independent circulatory arcs, with the right ventricle emptying into the aorta and the left ventricles into the pulmonary artery. In such a condition the ventricles are of the same size and generate comparable pressure. Since the systemic and the pulmonary circulations are separate and closed, the presence of left-right shunts in the heart is necessary for postnatal survival. This anomaly is compatible with life only if an atrial and ventricular septal defect and an associated patent ductus arteriosus accompany it, but even with these anatomical compensations, the quality of the blood reaching the body is poor.



Congenital malformations of the vascular system



Patent ductus arteriosus


In the fetus, the ductus arteriosus allows pulmonary arterial blood to bypass the unexpanded lungs and enter the descending aorta for oxygenation in the placenta. At birth, closure of the ductus arteriosus must occur so that the lungs will receive an adequate flow of unoxygenated blood from the pulmonary trunk. The increase in oxygen tension at birth leads to inhibition of local prostaglandins and causes functional closure of the ductus, followed by anatomic closure during the ensuing weeks of life.


If the ductus fails to close, blood shunts from the descending aorta to the pulmonary artery. Patent ductus arteriosus is the most common cardiovascular malformation in dogs, with a breed disposition in Poodles, German Shepherds, Collies, Pomeranians, Cocker Spaniels, Maltese, English Springer Spaniels, Keeshonds, and Yorkshire Terriers making them particularly afflicted.


The consequences of a patent ductus arteriosus depend primarily on the diameter of the duct and the pulmonary vascular resistance. When pulmonary vascular resistance is normal, blood will shunt from the descending aorta to the pulmonary artery because the aortic pressure exceeds that of the pulmonary artery during all phases of the cardiac cycle. This results in increased pulmonary flow and increased venous return to the left atrium and left ventricle. Volume overloading of the left side of the heart causes left atrial dilatation, left ventricular eccentric hypertrophy and mitral insufficiency. Left-sided congestive heart failure may develop from volume overload. When pulmonary vascular resistance increases, left-to-right shunting decreases and right-to-left shunting develops.


Symptoms of patent ductus arteriosus are extremely variable. The most common sign found by physical examination is a continuous murmur often accompanied by a thrill at the craniodorsal cardiac base in an otherwise normal dog. The abnormal sound most frequently found with patent ductus arteriosus is referred to as ‘machinery murmur’ since it is heard continuously through all phases of the cardiac cycle. The point of maximal intensity of the murmur is over the main pulmonary artery, high on the left base, from where it radiates cranially to the manubrium of the sternum and to the right base of the heart. Frequently, a systolic murmur is evident over the left apex if mitral incompetence is present. As a rule the left side (aortic) pressure is greater than that of the right (pulmonary) side. The strong blood flow from the higher pressure system (aortic) circulation into the pulmonary circulation overloads the vasculature of the lungs, resulting in pulmonary hypertension and ultimately heart failure.


Surgical ligation of the patent ductus arteriosus is recommended in all cases of left-to-right shunting as soon as possible after diagnosis. Without ligation, at least 50% of the cases are expected to die within a year of diagnosis. Some dogs, presumably with small shunts, may live for many years. A less invasive surgical correction of the ductus is coil embolization via transcatheter delivery of thin metal coils.



Persistent right aortic arch


Persistent right aortic arch results from a failure of the right dorsal aorta to degenerate between the seventh dorsal intersegmental artery and the point of fusion of the paired aortae. Persistence of the right aortic arch has been found in cattle, pigs, horses, and cats, and it is fairly common in dogs. It is responsible for 95% of the vascular ring defects in dogs and is most frequently seen in larger breeds (e.g. German Shepherds, Weimeraners, and Irish Setters). This malformation can appear under different phenotypes: in one form, the right arch connection persists and the left one disappears, resulting in the arch of the aorta being on the right instead on the left side; in a second form, both connections persist, but the right one is only a fibrous remnant without a vascular lumen; in a third form, both connections possess the characteristics of a vessel, which results in a double aortic arch.


A clinical consequence of the persistence of the right aortic arch is a complete or partial vascular ring being formed around the oesophagus and trachea. This vascular ring is made up of the right aortic arch, the ligamentum arteriosum (the remnant of the ductus arteriosus), and the pulmonary trunk. It surrounds and compresses the oesophagus and the trachea. Signs of a vascular ring formation are found typically when the animal begins to consume solid foods. After eating, regurgitation of undigested food occurs. As a consequence, the oesophagus secondarily dilates cranial to the stricture producing a megaoesophagus cranial to the base of the heart.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Teratology

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