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British Heart Journal, I97I, 33, 203-2I3.

Extrinsic factors in the genesis ofcongenital heart disease'

Maria V. de la Cruz, Luis Mufnoz-Castellanos, and Bernardo Nadal-GinardFrom the National Institute of Cardiology, Mexico City, Mexico

The extrinsic factors responsible for the production of congenital heart malformations bothclinically and experimentally are reviewed.

The method to be followed in the investigation of extrinsic factors as teratogenic agents for thea heart and the great vessels both clinically and experimentally is studied.

With Saxen and Rapola's work as a starting point, an hypothesis isproposed on thepathogenesisof congenital heart disease based on the alteration of the morphogenetic processes which normallyparticipate in the development of the heart and the great vessels, such as the morphogenetic move-ments, growth, and degeneration, the disturbance of which originates those malformations.

The most common congenital cardiopathies are interpreted by combining this hypothesis withothers previously proposed by one of us (de la Cruz and da Rocha, I956; de la Cruz et al., I959,i1964) on truncoconal malformations, and ventricular and atrial septal defects.

The main objectives to be attained in a programme of prevention of congenital heart diseasecaused by extrinsic factors are pointed out.

The evidence that rubella virus causes con-genital heart disease (Gregg, I94I; Swan etal., I944; Swan and Tostevin, I946; Michaels

* and Mellin, I960); the discovery of the terato-genic action for the heart of the Coxsackie Bvirus (Brown, I966, I969); the discovery thatsub-clinical forms of viral diseases are terato-genous (Evans and Brown, I963; Brown, I966);the advances in epidemiology and immunologywhich permit the prospective studies of theviral diseases by means of their early sero-logical diagnosis (McIntosh et al., I954;McDonald, I958; Brown, I969); the recentdevelopment of the vaccine for rubella viruswhich provides preventive therapy (Marshall,Dudgeon, and Peckham, I969); and the recentstudies in genetics which point to the import-ance of multifactorial inheritance and itsinterrelation with the extrinsic factors in the

* genesis ofsome congenital heart disease (Nora,I968), have led us to review extrinsic factors

* as teratogenous agents for the heart.In this paper brief consideration is made of

the extrinsic factors as aetiological agents incongenital heart disease, both in their clinicaland experimental aspects, and the method to

j Received 5 March I970.1 Presented at the 'Jornadas Internacionales de Cardio-logfa', 20-22 October I969, Mexico City.

be followed in studying them is examined.An hypothesis is also presented on the possiblepathogenesis of congenital cardiopathies,which is valid for the extrinsic and intrinsicfactors as causative agents. General outlinesare given for the prevention of these diseasesin the particular case of extrinsic factors.

Aetiological factorsThe aetiological factors of congenital mal-formations are called teratogenous agents:these interfere with the normal developmentof the embryo, causing defects in it. In theirstudy one must consider the extrinsic factors,the intrinsic factors, and the interrelationbetween both.

The extrinsic factors are physical, chemical,or biological agents different from the em-bryonic genoma, which may act on it or onthe cytoplasm or on both, affecting the cellswhich are in the process of differentiation(Fig. I).

The intrinsic factors are apparently spon-taneous alterations in the desoxyribonucleicacid of the nucleus within the chromosomes.They are, therefore, of genetic origin. Theiralterations may be quantitative, such as in

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204 de la Cruz, Munioz-Castellanos, and Nadal-Ginard

EXTRINSIC FACTORSPHYSICAL, CHEMICAL, AND BIOLOGICAL

CELL IN PROCESS OF DIFFERENTIATION

F I G. I Diagram representing the action ofextrinsic factors on the embryonic cells in theprocess of differentiation.

trisomy, translocations, and deletions, or

qualitative, such as in dominant or recessive

inheritance, linked to somatic or sexualchromosomes, and multifactorial inheritance.The division of intrinsic and extrinsic fac-

tors is mostly conventional, since they are

both intimally interrelated. For instance, it isa well-known fact that the effect of drugs withteratogenic action (extrinsic factor) depends onthe species or the strain used, whose differencelies in their genotype. Both factors are presentin the genesis of congenital malformationsand the division into intrinsic and extrinsic isone ofpredominance and not of exclusiveness.The analysis of teratogenous agents will beconsidered from the clinical and experimentalpoints of view.

Clinical studies The clinical studies haveusually referred to viruses (Gregg, I94I;Brown, I966; Manson, Logan, and Loy,I960), hypoxia (Alzamora et al., I953;Espino-Vela, I967), drugs (Lenz, I962;Smithells, I966), maternal hormones (Hoet,Gommers, and Hoet, I960), and radiation(Hicks and D'Amato, 1966). The clinical in-

vestigations have proved that hypoxia (Alza-mora et al., I953; Chavez et al., 1953;Espino-Vela, I967), rubella virus (Gregg,I94I; Michaels and Mellin, I960), and Cox-sackie B virus (Brown, I966, I969) are terato-genous for the heart.

HypoxiaStatistical studies have proved that there is ahigher incidence of congenital heart diseasewith arteriovenous shunt in children born inregions at an altitude of about 3000 metres andover above sea-level, as compared with popu-lations at sea-level (shown by Alzamora et al.I953), comparing the cities of Junin and Limain Peru and those of Chavez et al. (I953) andEspino-Vela (I967) at the altitude of theMexican plateau. In Junin, ventricular andatrial septal defects are more common, andpersistent ductus arteriosus is more commonon the Mexican plateau. These clinical find-ings suggest that hypoxia is a possible causalfactor, and this in turn is supported by theexperimental work of Ingalls, Curley, andPrindle (I952) who proved its teratogeniceffect in mice by producing interventricularseptal defects.The frequent occurrence of congenital

heart disease has been pointed out in childrenborn of mothers with congenital heart disease(Ingalls, I960). This fact could be due to anintrinsic factor related to sex or to an extrinsicfactor represented by hypoxia of maternaltissues. It seems as though this latter is thecausal factor but a study in large populationsis needed in order to reach some validconclusion.

VirusThe rubella virus causes patency of the ductusarteriosus and ventricular septal defect withgreater frequency, and less commonly tetradof Fallot, transposition of the great vessels,and aortic coarctation (Ingalls, I960). Recentstudies have further clarified the pathogenesisof its action on the embryo. The virus pene-trates the embryo through the blood stream,destroying the placental barrier where it be-comes fixed in some of the embryo's organs,and causing cellular death and inhibition ofcellular multiplication. When these disordersare severe, irreparable lesions are produced incertain organs, which are expressed as mal-formations. When they are slight, they causea delay in the growth of organs (Tondury andSmith, I966). It has also been pointed out thatCoxsackie B virus causes cardiomyopathy inthe foetus when the mother has been affectedin the latter months of pregnancy (Kibrick

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Extrinsic factors in the genesis of congenital heart disease 205

and Benirschke, 1956, I958), and gives rise tocongenital cardiopathies when the infectiontakes place during the first months of gesta-tion (Brown, I966, I969).

Experimental studies The experimentalstudy of extrinsic factors has proved that thefollowing agents cause congenital cardio-pathies: a diet deficient in vitamin A (Wilsonand Warkany, 1950; Wilson, Roth, andWarkany, I953b), a hypervitaminic A diet(Kalter and Warkany, I96I), a deficiency ofpteroilglutamic acid (Nelson, I960; Baird etal., I954), a deficiency of riboflavine (Kalterand Warkany, 1957; Nelson et al., I956),trypan blue (Fox and Goss, 1958; Wilson,I955), hypoxia (Ingalls et al., I952), actino-mycin D (Tuchmann-Duplessis and Mercier-Parot, I960), experimental haemodynamic

s disturbances of the embryo (Rychter andLemez, I96I), alantoid fluid (de la Cruz et al.,I963), radiation (Wilson, Jordan, and Brent,1953a; Le Douarin, I963), and hypothermiaduring incubation of the chick embryo (de laCruz, Campillo-Sainz, and Muiioz-Armas,I966).

MethodologyTeratology is a branch of science which lacksa specific methodology and uses the methodsof other disciplines such as epidemiology,genetics, and embryology. For this reason theefficacy of these is doubtful in the investiga-

A tion of aetiology and pathogenesis of con-genital defects. The selection of the methodwill depend fundamentally on the type of

. study to be undertaken, either clinical orexperimental.

Clinical aspect The clinical method is* statistical, with a limitation due to the factthat samples obtained are not a true repre-sentation of facts, since many of the embryoswith malformations are absorbed in utero andaborted in very early stages of development.Another difficulty of the statistical methodsin the clinical study of teratogenesis is the im-possibility that all the factors remain constant,both for the group under study and for thecontrol group. Some of the factors that mayaffect the action of the teratogen, eitherinhibiting it or favouring it, are socio-economic, geographic, and racial conditionsas well as maternal pathological antecedents.

Statistical studies may be prospective orretrospective. Each one has precise indica-

3vtions. In the case of virus, though the firstreports which began with the work of Gregg(1941) on rubella were retrospective, the dis-

covery of new teratogenous viruses for man,the advance of the techniques for detection ofantibodies and, especially, the fact that sub-clinical infections are the ones that mostcommonly cause congenital malformations,have oriented the epidemiological investiga-tions towards a prospective examination ofpregnant women. This is done by means ofserial serological measurements of viral anti-body content in every woman immediatelyafter the diagnosis of pregnancy is made(Brown, I966, I969). In addition, anatomicaland histological examinations (Nishimura,I969) and virus cultures of abortions shouldbe made. Finally the clinical study of newbornchildren up to those of school age should beundertaken.

Despite the fact that prospective studiesare better, retrospective studies should notbe discontinued since they may provide thebases for the discovery of new teratogens,and because when one of them appears inman unexpectedly, it is the only method thatcan be applied.

In evaluating the results of prospective andretrospective studies in the specific exampleof congenital cardiac malformations, it mustbe kept in mind that some malformations areasymptomatic during the first years of extra-uterine life, as for instance peripheral stenosisof the pulmonary artery branches and atrialseptal defect. Therefore, one must proceedwith the observation of children up to schoolage. Other malformations are asymptomaticthroughout the entire life span, such asmirror-image dextrocardia, ventricular inver-sion with transposition of the great vesselswithout associated malformations, and someanomalies of the aortic arches which can onlybe diagnosed by means of careful cardiologicalstudy. On the other hand, in the newbornthere are functional heart murmurs whichmimic congenital cardiopathies and only theircourse will allow us to discount heart disease.

Experimentation The methodology to befollowed in investigating the role of teratogensin congenital heart disease is set out below.

Choice of animal modelThe type of aniimal to be used in the investi-gation of the teratogenic action of extrinsicfactors is that animal, the control group ofwhich shows no spontaneous congenitalcardiopathies, with significant statistical value.Such is the case with White Leghorn chickenswhich do not show spontaneous interventricu-lar septal defects, while the S line ofthe BrownLeghorn strain, which has a high spontaneous

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incidence of these malformations (Rychter,Lemez, and Siller, I960), constitutes an in-adequate animal model for the study of theaction of extrinsic factors in teratogenesis ofthe heart. The choice of animal will also beconditioned by the possible teratogenousagent which will be subject to investigation.For instance, in the case of diets and drugs(Wilson and Fradkin, I969), species will beselected according to the similarity of theirmetabolism to that of man, and in the case ofthe virus those species or races will be chosenwhich are susceptible to them.The control group and that subjected to the

action of the possible teratogen must be con-

stituted by a population with a significantstatistical value. Both groups must be sub-jected to the same conditions except theteratogen which is to be investigated in one

of them. Conditions that must be maintainedconstant are: race, strain, diet, density ofpopulation, climatic conditions, immuniza-tion, and age of parents.

Age of embryoAccording to concepts established by Wilson(I965), teratogenic agents produce their actionduring a certain period of development whichis called the 'highly teratogenic stage' and ischaracterized by the maximal susceptibility ofthe embryo to the teratogen. The 'highlyteratogenic stage' is preceded by an em-

bryonic stage 'not susceptible to teratogene-sis', in which the embryos do not have a

teratogenic response or their response islethal; it is followed by another stage, 'pro-gressive resistance to teratogenesis', in whichthe embryo becomes more and more resistantto them until it loses its capacity to respond,and merely shows a delay in overall growthor a similar pathology to that observed in thepostnatal period (Fig. 2).The stage 'not susceptible to teratogenesis'

corresponds to the blastular stage of the em-

bryo, one in which the great majority ofembryos resist teratogenic actions or die(Fig. 2). While the exact mechanism of the

FIG. 2 Diagrammatic representation of the three general periods of ontogenetic developmentof mammals. For each period the main events of development and their differentsusceptibility to the action of teratogens are indicated. (Based in part on thework of Wilson, 1965, p. 252.)

FERTILIZATION B L A ST U L ATI0 N l

Pre-Usalno

differentiation( susceptibleto

period teratogenesis

GASTRULATION TUBULATION

period Highlysusceptible

of early ldifferentiation _ teratogenesis

Early Morphogenetic , Late MorphogeneticMovements Orgor Movements

ORGANOGENESISDevelopment of Develmnt of Development of

Kidney Reproducti rg Intestle InCreaSInglyIrg a(7\ resistant to

of advanced teratogenesisorganogenesis ~./ with increasing

Secondary Induction Degeneration Differential Growth Growth age

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lack of teratogenic response is unknown, thiscould be explained, because in these develop-mental stages there are regulating mechan-isms by means of which the damaged cellsare replaced by other cells capable of substi-tuting them in the morphogenetic processes.If cellular damage were extensive enough todestroy great populations of cells, the responsewould be lethal.The maximal period of susceptibility or

'highly teratogenic period' begins with theestablishment of the blastodermic layers, andit varies with the different species (Wilson,I965); it starts on the sth day after fecunda-tion in the hamster and in the mouse, on the8th day in the rat, on the gth day in the rabbit,on the ioth day in the monkey, and from thei ith to the I2th day in man. In fowl, thesusceptibility to teratogens takes place a few

* hours after the beginning of incubation, dueto the fact that the pregastrulatory stages havetaken place in the genital tract of the motherbefore laying the egg. During that stage aseries of developmental processes takes place,

, which have an orderly and interrelated se-quence. The action of the teratogen will de-

* pend on the process that has been altered and

on the disturbances that it in turn originateson the subsequent processes. This periodstarts with the gastrulatory morphogeneticmovements by means of which the differentpresumptive organ-forming areas are placedin space in such a manner that they may inter-relate in order to lead to the processes of pri-mary induction. The organizing processes andprimary induction processes take place simul-taneously in an integrated fashion and theyare of the utmost importance for the subse-quent development of organs (Fig. 2). In thisstage, teratogenic agents greatly affect thegeneral morphogenesis of the embryo (Fig.3).At the end of the gastrulatory morpho-

genetic movements the presumptive organ-forming areas lose their capacity for regula-tion, the determination of them is producedand the primary induction systems are estab-lished, at which precise time, cellular differen-tiation at molecular level begins. It could bethat, at this stage, extensive and severe mal-formations may be produced which affectnumerous organs.Once the establishment of the specific

organ-forming areas has started, there begin

FIG. 3 Chick embryos after 4 days' incubation, stained with haematoxylin. (A) Embryoinoculated at 17 hours of incubation with active influenza A virus. Observe the great

-alteration of normal configuration. (B) Normal embryo.

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2o8 de la Cruz, Munioz-Castellanos, and Nadal-Ginard

the secondary morphogenetic movements, theprocesses of secondary induction, of degenera-tion, and of differential growth, all of whichparticipate in the peculiar morphogenesis ofeach organ (Fig. 2 and 4).Though the specific organ-forming areas

are determined simultaneously, the morpho-logical and physiological differentiation of theorgans takes place usually in different stagesof development, and there is a period ofmaximal differentiation for each one of themin particular. Furthermore, in the same

developmental stage different organs are

undergoing simultaneous maximal differen-tiation processes. These may be the reasons

why the same teratogen acting on differentstages of development produces differentmorphological alterations (Saxen and Rapola,I969; Nelson et al., I956) (Fig. 5), and whydifferent teratogenic agents acting at a certainstage produce characteristic syndromes (Run-ner, I959). Besides, different teratogens actingat different stages of development, affecting acertain metabolic cycle, give rise to the same

type of defect (Saxen and Rapola, I969).

Choice of teratogen agent, dose, route ofadminis-tration, and other modifying factorsThe choice is conditioned by the object of theinvestigation.The effective dose is that which modifies

the normal development of the embryo with-out causing early death and without beinglethal to the mother. Their range of action isnarrow and is named 'teratogenic dose of theagent'. A smaller dose allows the normaldevelopment of the embryo (Wilson, I965);therefore, not every dose of a teratogenicagent has a teratogenic action, and besides, inthe case of certain drugs there is not a directrelation between the teratogenic and thetherapeutic dose. A teratogenic dose is alwaysinseparable from the age of the embryo andits genotype.The total teratogenic dose may give rise to

different malformations depending on whe-ther it is given as a single dose or in severalportions. Experimental data indicate that a

single, acute, and short treatment is more

effective in the production of malformationsthan a long treatment, because the embryo

FIG . 4 Diagrammatic representation of the two general periods of heart differentiation inbirds and mammals. The principal morphogenetic phenomena and the correspondingsusceptibility to the action of teratogenic agents in each one of them are shown.

GAST RU L AT ION -TUBULATION

Period ltHighlyofiffearentlytionl (t) I t) R (C3 |susceptible

differentiation eaoeeiHeart-Forming Mor_getic Fusion of Torsion of Cardiac tube teratogenesisareas movements of primitive

-wortf gtubulhboareas

THE PARTITIONING OF THE HEARTIncreasingly

Period ~-...4resistant

of advanced toorganogenesis teratogenesisIorganogenesisliS ~K|withincreasing

Septal Growth Degeneration age(Interatrial foramen secundum)

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sr

FIG. 5 Developmental periods of the internalear, lens, and heart, sensitive to the terato-genic action of rubella. The numbers in theexternal circle indicate weeks of development.Notice that during the 7th week, the threestructures are affected simultaneously. (AfterB. Mayes, Triangle, 3, 10, 1957.)

under the prolonged action of noxious agentsusually dies (Fraser, I964).The route of administration of a teratogenic

agent may cause the disappearance of itsI teratogenic action, or transform into a terato-

gen an agent that was not teratogen given bya different route (Fraser, I964). These changesmay depend on the absorption mechanism ofthe metabolic subproducts and on the dura-tion of their action on the embryo.The vehicle of the drugs and the means of

suspension of the viruses may have in them-* selves a teratogenic action, and in the particu-

lar case of drugs if the vehicle combines withthem forming a new compound, they maytransform them into teratogens or neutralizetheir possible teratogenic action.There are a number of environmental fac-

tors such as undernutrition, climate (Kalter,i1959), crowding, infections, and endocrinediseases in the mother, which may in them-selves be teratogen or, without being so, maymodify the action of the possible teratogen,either increasing it or inhibiting it.

Examination of results* The material obtained is divided for study

into two groups: pre- and postnatal, since themethod followed for the diagnosis of cardio-vascular malformations is different in each oneof them.

In the prenatal study the embryos andfoetuses should be examined periodically; inthe case of fowl, the embryos and foetusesthat have died during incubation should bestudied, and in mammals, besides the studyof spontaneous abortions, it will be necessaryto sacrifice periodically some pregnant femalesin order to analyse the dead embryos andfoetuses that were not aborted and that wouldbe absorbed in utero. The survivors of thesame litter should likewise be examined. Theembryos whose cardiac tube is in the stage oftorsion should be stained and block-mounted.In later stages the heart will be examined bymicrodissection, and in certain cases, histo-logical techniques should be used. First, themorphological age of the embryos should bedetermined and later the resulting cardiovas-cular morphologies must be compared withnormal individuals of the same morphologicalage (de la Cruz, Mufioz-Armas, and Mufioz-Castellanos, I969). Thus, the presence of acommon truncus arteriosus in the chickenembryo of 4 days of age is normal, while it ispathological starting on the 5th day; an atrio-ventricular canal is normal on the 4th day andit is abnormal from the 6th day on (persistentcommon atrioventricular canal), which leadsto the inference that it is necessary to know indetail the normal embryology of the animalselected for experiment.

In the case of viruses as teratogenic agents,it is necessary to show the multiplication ofinfecting particles in the embryonic tissuesduring the first hours after incubation (de laCruz et al., i963).

In the postnatal study of animals, every new-born animal must be sacrificed in order toprove if the possible teratogen producedcardiovascular malformations. When certaincardiopathies are produced experimentally,the experiment must be repeated under thesame conditions, but the adult animals shouldbe sacrificed in order to learn the natural his-tory of the malformations; for instance, ifinterventricular septal defects were producedit is necessary to know if pulmonary hyper-tension appeared, if a prolapse of the sigmoidaortic valve cusps took place, and also theevolution of the ventricular enlargements im-posed by the haemodynamics. If the animalsare sacrificed exclusively at an adult age, thestatistical analysis of ventricular septal defectwill not be true to fact, since many of the ven-tricular septal defects close spontaneously inthe first days of postnatal life (Siller, I958).The method of study is micro- or macro-

dissection, depending on the size ofthe speciesand the age of the animal; in selected cases

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2io de la Cruz, Muinoz-Castellanos, and Nadal-Ginard

this should be complemented with histologicaltechniques and tissue culture techniques.

Hypothesis on pathogenesisThe morphogenetic movements,' induction,2,growth,3 and degeneration,4 are the fundamentalprocesses that determine the development ofform, structure, and function of an organ. Theintimate nature of these processes is unknown.In the development of a particular organ, one ormore of these processes participate.

In normal organogenesis of the heart, morpho-genetic movements, growth, and degenerationparticipate. It is unknown at the present time ifthere are induction processes. If we examine in ageneral way how these processes participate inthe development of the heart, we find that mor-phogenetic movements determine the fusion ofthe two cardiac primordia (DeHaan, I963a, b);growth processes are those that participate in thedevelopment of the interventricular septum(Streeter, I948), of the septum separating theascending portion of the arch of the aorta fromthe pulmonary artery trunk (Kramer, 1942), thevalvular apparatus (Kramer, 1942), the cardiacchambers, and the interatrial septum in whichthere is also a degenerative process (Fig. 4). Thislatter factor is the reason for the normal disappear-ance of the aortic arches (Congdon, I922).Using the criterion established by Saxen and

Rapola (I969) for the classification of congenitalmalformations according to the altered morpho-genetic processes, we divide congenital cardio-pathies into three large groups and their respectivesubgroups: those due to disorders in morpho-genetic movements, in growth, or in degeneration(Fig. 6).

It is important to emphasize that the abnormalmorphology of the heart is not determined onlyby the alteration of the processes mentioned, butalso by the secondary malformations created bythem and pre- and postnatal haemodynamics.

Disorders of morphogenetic movements(Fig. 6) This group comprises only cardia bifidawhich originates because of a failure of the twocardiac primordia to unite (DeHaan, I963a).

Growth disorders (Fig. 6) These are dividedinto three subgroups: excessive growth, ectopicgrowth, and absence of growth.

Excessive growthThis group comprises aortic valvular and pulmon-ary stenosis, both of which are due to an excessive

1 Morphogenetic movements are the oriented andirreversible displacements of a group of cells of theembryo which participate in the moulding of it and ofits organs.2 Embryonic induction in general is the influenceexerted by one embryonic structure on another one,determining their differentiation.3 Growth is the increase in a cell population by multi-plication of its elements.4 Degeneration is the death of cellular groups, whichnormally takes place during embryonic development.

SECONDARYMORPHOGENETICMOVEMENTS4 4

DELAY INTERRUPTION

Cardia bifida

GROWTH

I EXCESSIVE ECTOPIC ABSENT4 ~~~44Aorticond pulmonary Tranmpositon of Atrial septal defect,

valvulhr stenosis great vessels foramen primum typeElsenmenger conplex Conmnon atriaventicular canalTaussig-Bing complex Congenital absence of

aortk and pulony vatv2sieiraiogy OT ralol

DEGENERATIONEXCESSIVE1EC OPIC * ABSENT

Atriol septai defect, Coorctation of oorta Pateit ductusforamen ovde type arteriosus

Complete interruptionof oortic arch

FIG. 6 Classification of the most commongenital cardiopathies according to the type ofalteration of morphogenetic processes.

growth of the primordia of the valves, which leadsto a narrowing of the valvular orifice (de la Cruzand da Rocha, I956).

Ectopic growthIn this group we find numerous congenital cardio-pathies, among which are transposition of thegreat vessels, Eisenmenger's complex, Taussig-Bing complex, and tetrad of Fallot.

Transposition ofgreat vessels It originates due tothe ectopic growth ofthe truncoconal ridges whichdevelop in a straight fashion (de la Cruz and daRocha, I956) instead of having a normal rotationof i8o degrees.

Eisenmenger's complex This is due to an ectopicgrowth of truncoconal ridges which develop witha rotation of less than I80 degrees and above godegrees, affecting exclusively the conal portion ofthe ridges. This leads to the anterior position ofthe pulmonary artery and the posterior positionof the aorta, to the right of the pulmonary artery.In this malformation, the conoventricular flange isalso involved, since its late disappearance causesthe great vessels to arise from the right ventricle.Ventricular septal defect is due to the failure toalign between the conal portion of the truncoconalseptum and the primitive interventricular sep-tum. The dilatation of the right ventricle and ofthe pulmonary artery are due to haemodynamicdisorders.

Taussig-Bing complex This malformation iscaused by the same fundamental disorders whichgive rise to Eisenmenger's complex, thoughdextroposition of the truncus-conus of the em-bryonic heart is of lesser degree.

Common trunk

Ventricular septal defect

Tetrad of Fallot The typical form is due to theectopic origin of the truncoconal ridges which are

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normally rotated i8o degrees. The developmentof these truncoconal ridges takes place within theterritory of the truncus-conus, which normallybelongs to the pulmonary artery (de la Cruz andda Rocha, 1956), and causes a mixed infundibulo-valvular stenosis and a diminished calibre of thepulmonary artery trunk. Ventricular septal defectis caused by the lack of alignment of the conalportion of the truncoconal septum with the primi-tive interventricular septum. Right ventricularhypertrophy is the result of haemodynamic

* disorders.

Absent growthIn this group the following malformations are in-cluded: foramen primum, common atrioventricu-lar canal, ventricular septal defect, agenesis ofaortic and pulmonary sigmoid valve cusps, andcommon trunk.

Foramen primum This malformation is causeda by the lack of growth of the septum primum and

the septum secundum at their caudal portion(Oliveira Solari et al., I962).

Common atrioventricular canal This cardio-pathy originates as a result ofthe absence ofgrowthof one or both the dorsal and the ventral atrioven-tricular canal cushions (de la Cruz et al., I964).Atrial and ventricular septal defects are secondaryto the alterations of those cushions.

Ventricular septal defect The different types ofisolated ventricular septal defect are due to theabsence of growth of one or several of the em-bryological components which normally partici-pate in the development of the ventricular sep-tum (de la Cruz et al., 1959).

Agenesis of aortic and pulmonary sigmoid valvecusps These are produced by the absence ofgrowth of the primordia of the cusps (de la Cruzand da Rocha, I956).

Common trunk This is caused by the lack ofgrowth of the truncoconal septum (de la Cruz

* and da Rocha, I956). Ventricular septal defect issecondary to the absence of this septum which

+ participates in the normal formation of the inter-ventricular septum.

Disorders of degeneration (Fig. 6) These aredivided into three subgroups: excessive degenera-tion, ectopic degeneration, and absence of

* degeneration.

* Excessive degenerationThis group includes some of the atrial septal de-fects of the foramen ovale type, due to an exces-sive, greater than normal degeneration of the areaof the septum primum which appears within theannulus of the foramen ovale (Oliveira Solari etal., I962).

+ Ectopic degenerationThis group includes especially coarctation of theaorta, complete interruption of the isthmus of the

aorta, and atrial septal defect of the foramen ovaletype.

Coarctation of the aorta This malformation isdue to a process of incomplete degeneration of theleft fourth aortic arch or left aortic dorsal root.These vessels do not undergo this process duringnormal development.

Complete interruption of the aortic isthmus It is amore severe degenerative process taking place atthe isthmus of the aorta than that causing coarcta-tion of the aorta.

Atrial septal defect offoramen ovale type malforma-tion This defect is caused by an ectopic resorp-tion of the septum primum, at the area limited bythe annulus of the foramen ovale (Oliveira Solariet al., I962).

Absent degenerationNumerous malformations of the aortic arches be-long to this group, which are represented bypersistence of some which should normally dis-appear. These include persistent ductus arteriosus,due to the lack of degeneration of the distal por-tion of the left sixth aortic arch.

Following these criteria the majority of cardiacand vascular malformations can be adequatelyinterpreted. Only the most representative mal-formations have been analysed in order to illus-trate the disorders of morphogenetic processes ofthe heart.

Prevention: general outlineThe scarce information obtained from thestudies undertaken on intrinsic factors in thegenesis of the congenital cardiopathies, andthe increase in the number of people withthese malformations who have prolongedtheir life as a result of surgical treatment whichallows their procreation, make it difficult topractise preventive medicine.

Prevention of congenital heart diseasecaused by extrinsic factors, on the contrary,has been enriched by the demonstration ofthe importance of extrinsic factors in the ex-pression of multifactorial inheritance, a morecommon transmission mechanism of thosemalformations due to intrinsic factors; thecreation of a vaccine for rubella virus whichpermits prevention of cardiopathies producedby this virus; serological tests of antibodiesagainst numerous viruses, which make pos-sible massive prospective studies in order todiscover new teratogenic viruses for the heart;the more precise clinical diagnosis of con-genital heart disease and the improved know-ledge of the natural history of many of them,as well as the fact that a series of environ-mental factors such as undernutrition, hy-poxia, crowding, endocrine disease of the

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mother, and some infectious diseases may beteratogenic in themselves, or, without beingso, may increase or enhance the action ofknown teratogens or may transform intoteratogens some agents that normally werenot so.The previous considerations should serve

as a basis for the elaboration of preventionprogrammes against congenital heart disease,in which vaccination against rubella, the sys-tematic serological study of pregnant women,the early diagnosis of congenital heart disease,and the observation of children up to schoolage in any prospective study of a possibleteratogen for the heart, together with theimprovement of socio-economic conditions,are the important goals to be attained.

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