338
JACC Vol . 18, Na 2 Annu al 1991911-42
c'H 1 .11 INI H10, 1, I NiIIJCARDITiS
Prevention of infective endocarditis . Good daily oral byglene is emphasized. Foods that induce caries should be minimized or avoided . The teeth should be cared for by twice daily brushing with a soft bridle toothbrush and regular gum stimulation and flossing . k dentist or hygienist should be seen twice yearly . It is believed that fluoridatica of drinking water plays a favorable rob; . and daily "gingival degerming" with certain mouthwashes or hydrogen peroxide may decrease plaque formation and gingivitis . Meticulous skin care is also to be emphasized . Patients should meticulously avoid squeezing pimples or pusruivs and should desist from nail biting or picking with the accompanying risk of paronychiu and periungual infection . Prophylactic advice best begins in childhood to instill good habits . Chemopnphvlaris requires direct medical intervention and advice . To be successful, recommendations must he not only bacteriologically effective. but also acceptable to the patient and physician in terms of cost . case of administration haute and duration) and few if any side effects . A complex, costly and painful regimen . no natter how ellective, results in lack of compliance and no protection . The selection of an antimicrobial agent for prophylaxis is based on anticipation of which organisms are likely to be confronted and on the desirability of bactericidal activity. In patients at highest risk of infective endocarditis (those with a prosthetic device, a surgically created systemic to pulmonary artery shunts or previously documented infective endocarditis )especially recurrent endocarditis)), parenteral regimens have been advised . However, risk categories have been rendered less important with the current recommendation of oral amoxicillin for dental and upper respiratory procedures (12 .13) . Oral amoxicillin is absorbed better than is penicillin V from the gastrointestinal tract, with higher and more sustained serum levels. For most patients in whom oral penicillin V was previously recommended, that choice remains acceptable 1131 . In patients with penicillin allergy . use of erythromycin, especially erythromycin cthylsuccinale and stcaratC,
is giving way to use of oral clirdamycin. Details retarding the preceding recommendations are available in the current American Heart Association statement 1121 on prevention of bacterial endocarditis and antiinfective endocarditis prophylaxis .
References I.
Karl.. EL, Riuh H. Gersony W, Manning J .
,,,Deco
alluburutwe study of
enducnd,i, .mihe197w.emiAn,
u rpetlrnts .hu
have undergone cardiovascular surgery. Cheat, ,,o 1979.59:3 17-35, '- . DecIber D, Iksbs LL . Chakem S. Fullol's
leis
logy
n 20
year surgical
ioiluw-up, Br Heart 1 1971 :}1 :t2 12 . 3 [maciho JS . Belcher P. Knight Wit. Infecuon of modified Bialnek shams . Br Heat J 1987 .58 :287-90, 4.
Johnson DH . Rosenthal A . Nadas AS . A funs year review of bacnrial
rnd,xard,i, in infancy and sh,Whad . Circulation 1975:57 :581-8. 5, John- CM . Rhodes KH . Pediatric endaardai •. Mayas Clin Pros 1982 : 57:86-94 . 6 . Kaplan EL Infertive enda.arduts in the pediatric age group . An over-- . In: Kaplan EL . Tannin AV . ads . Inteavve Fndocarditis. An American Hero Association Symposium . Dallas . TX : Amennan Hean Asacialiml. 1977 :$1-4 .
7 . Gersuny WM . Have, CJ . Bacterial endoearditis in patients with pulmonary sIeno,i, . anti[ sIcno,is or venMcular septa) defect . Circulation 1977.S61sappl 11 :1",'d_7. 0. Everest ED. Hirschmann IV . Transient bacteremia and endocarditis prupht,!anis: a nview. Medicine 1977 :56:61-77. 9. Corgi, G . Erbcl R . Hennahs KS. Wenchel H.M . Worst H-P. Meter J . Posaive blood cultures during Iansesophageal echocardiography . Am J Cardiol 1998:65:1404-5. 10. Chandraseken K . uansal RC . Mints 4S . Ross 1J . Shah PM . Impact of hansesophageal color flow Doppler echocardiography in current clinical practice . Echocardiography 1990 :7 :115-45 . If. Foster E. Kusumata FM . Sobol SM . Schiller NB. Streptococcal endocarditis temporally related to tmnaesopheural echavardio
vphy,
l Am
San Echo 1990:5 :424-7 . C . Daaani AS. Barn AL, Chung KJ. el al. Prevention of bacterial andocarth . tis, recommendations by the American Heart Association . JAMA 1990: 264:2919-222 . 13 . Endoearditis Warkitg Party of the Banish Society for A ;.:isrimubial ehemomerapy. Anhhintie prophylaan of mieettve crdaardin . I_ao-c, 1990:31:88-9.
Assessment of Genetic Risk in Congenital Heart Disease EDMOND A . MURPHY, MU . REED E, PYER:-IZ, MU . PHU
Most studies an the genetics of congenital heart diseases have devoted much effort to traditional questions . questions that are often not central to the issue . There has been little attention to defining and exploring the fundamental problems to which coherent inquiry can be directed . After long inaction, interest in the genetics of congenital heart disease is slowly reviving. The approaches are on several quite dif-
ferent fronts: cytogenetic, hinchemical, analytic, statistical, mathematical and clinical. Though quite diverse and nut easily unified, they are by no means irreconcilable . The prospects are promising, exciting, even revolutionary ; but at this stage, the knowledge is germinal only and not ready for clinical application. We (1) recently reviewed some of this knowledge .
JACC Vol . 18. Na . 2 Aaron ts'1O11-i?
MURPHY AND PYERITZ AsSESSSte,uT tie GENETIC RISK IN CONGENITAL . HEART DISEASE
The key questions, however . may seem bizarre To the clinician. This brief report is no place to expound these leads . Our concern here is much more practical . We stress, again that what follows is tentative : at best provisional in matters of fact and even in its broad relation to what the final solutions may he .
Etiology and Pathogenesis the best and most useful statements about risk depend an .he resolving power of the data and on the part that explicit and formal reasoning is allowed to play in the analysis . An excellent example of the noncommittal approach is that of Higgins . (2} At one extreme, the usual method of epidemiology makes little attemp[ at actual rational understanding . The classic example, congenital heart disease due to maternal rubella- was well established in the firs) place on purely empire grounds. It was only when the relation was shown that the pathogenesis was explored. For the most par' . epidemiology pays little attention to basic mechanisms- Any deeper understanding and any more precise assessment of risk call for some degree of modefiny . that is, same cunjeclore about how the process operates . In some aspects of genetics. there are unusually persuasive grounds for such . The models : in others, the grounds are more conjectural current primitive understanding o'i the etiology of mast forms of congenital heart disease re',lects the gross neglect of modeling. We know of many genetic types of congenital heart disease . some Mendelian . some chromosomal . sonic perhaps cytoplasmic . some chemical : we know of several cnvirunmental factors (infections such as rubella and cytomegalovims: intoxication inch as ethanol and vitamins ; metab!ic factors such as maternal diahetesl . But few of them lead to precise and secure assessments of risk, the main reason is That nothing isknuwn of pathoger'esu . 11 dvCs little good to patch up disparities in the data by vague notions I"variable expressivity ." 'incomplete penetrance ."multifactorial inheritance." "interaction' 'I . patches that are lacking it.. precisely defined properties that can pe investigated cogently, falsified . verified and authenticated At the present time, the clinical cardiologist must be content to keep track of a few proved risk factors- The means of predicting the -mhined effect of cnnirunmental and genetic risks are exquisitely precise in the hemolytic anemia favism for the very reason that the pathogenesis Is well understood . However, in congenital heart disease . pathogenetic insights will not be available in the foreseeable future : when they arrive . they may have startling properties .
Practical Assessment of Risk This topic . the gist of our discussion . will reflect these notions of degree of explicitness, The field is controversi :d and it is best to confine ourselves to what is agreed on among reputable authorities .
339
Mendetiziug trails. Quite a formidable list (3) can be compiled of congenital heart disease that seems to be inherited as Mendelian (single-gene) trails. sonic of them defects of structure (like the Holt .Uram syndrome), some of tissue (like Marfan's syndrome( and some of function (like the Jerveli-Lunge-Niclsen syndrome of QT Interval prolongalion . ventricular tachy'cardia and deafness) . The family Patterns are often irregular . perhaps because the phenotype is uncomfortably far removed from the gene action . More systematic collection of data and more sophisticated attention to minor changes in "unaffected" relatives would doubtless improve the underctauding ol'the pattern and the prediction of recurrence risks . 'I he advantage of Mcndelfan traits is that the rules for genetic counseling can be svgternatically (though not trivially) derived from Mende:inn >trinciples (4) . However . Mendclian congenital hear[ disease, though in aggregate perhaps not uncommon, is individually rare . Chromosome abnormarilies. Congenital heart disease may occur as a feature of chromosomal anomalies (the syndromes of TerOCr and Down . lrisomy-13) . The occurrences of congenitzi Sean disease are irregular, and at present there are theories but no accepted explanations for them . The most cie can say is that the occurrence of these disorders should alert the clinician to the possibilities of the cardiac lesions . Specific fawfty recurrence. The theory of thresholds (4) suppose, that the phenotype for congenital heart disease is or is not present depending or whether the value of some hypothetic quantitative [rail e .tceeds a threshold. The fact that the probsnd is affected and therefore has exceeded this threshold makes it Inure likely that any close relative will also exceed it. This model in congenital heart disease has been explored largely by Nora and Nora0) and by SanchezCascos to with considerable success . go[ the proper use of the full theory in genetic c ounseling . i s not only complex but tedious and no Clinician has satisfactorily applied it in pedigrees with multiple affected siblings- Moreover- there has been little concern on the part of either clinicians or theorists in pursuing the implications of the hypothetic quantitative trail. The one useful working principle front it is that under usual circumstancesm the average number of abectcd first-degree rclativex is prnpnnional to the square root of the frequency of the trait in the population at large. Thusa if a trait has a frequency of I in 10.0110 . the expected proportion would be I in IOo or I (note that 1%. is a proportion : it is not the probability of recurrence . which in any particular family increases with the number of affected relatives) . Nonspecific ramify recurrence risk . Many studies analyzing the "black box" recurrence risks in relatives according to the types of lesion in the prohand show that the cardiac phenotypes do not breed true . Relatives of a patient with defect A are themselves at higher risk than average of having defect A : they are also at somewhat higher risk of having other lesions (B and C . and so forth) . We may couple this
3411
P1 Ri (* 1 I'CI ( ;N%,%('1' ANO ('ONGIfNil ' :1L HLAk'I I715F`ASi' .
lack of specificity with the diversified )" plciotropic') characier of cantenlial heart diseases, even those hat seem to be Mendelian . 'Iogetiler they have given rise to the notions that ,hat is inherited is not unr~p4++fogir but uu+rppugeu'tir . The geneticist should he looking for unifying defects of develop . mental mechtmisms . not unity in their effects . ']'he risks of recurrence may be compared with the 5117r for dominant genes and 257 for recessive genes . The in . crease in risk for non-Mendelian traits is then small . One would have expected as much, fur a high recurrence risk (such as occurs in the simple Mendelixing cases) takes a heavy selective loll, so that the traits should remain rare . (To the clinician . congenital heart disease may appear to he rare . but among genetic diseases it is astonishingly common) . Massive empiric evidence confirms the predicted low recurrence risk- The average recurrence risk in congenital heart disease is usually not = J7r to 597 . the kind of risk figure one uses in counseling when all else fails . Needless to say . wherever an adequate history would furnish a more rational basis for calculating risk (lot' instance for the Jcrvell-LangeNielsen syndrome which is autosomal recessive). one would use that risk. Semispecific family recurrence risk . Between the extreme rigorof the Mendelian analysis and the nihilism of pure black box risk, there is a type of analysis that is growing in popularity. It is based on the notion [hat certain groups of lesions may occur together more often [ban others because they are more closely related in etiology and pathogenesis . such as hemodynamics or contributions from the neural crest . The classification of congenital heart disease by Clark (7) is an attempt at such a rational ordering . One instance for which there is now excellent evidence is defects of the left
tArc V.,) Is. No .2 Augurs -1111-42
ventricular outflow tract . Too narrow a concern with anatomic specificity would obscure this valuable c lue . a s would too indiscriminate a pooling of data. The relation can be usefully if tentatively interpreted as the result of common hydraulic factors at work . Conclusion Most of our useful common knowledge about the genetics
of congenital pearl disease appeals to a few rational principies, which may be somewhat refined by better phenotyping, linkage analysis and exploration of candidate genes . All the current indications are that the major advances in this field in the next 10 years will come from a deeper understanding of pathogenesis and the accurate measurement of the effects of morphogenetic genes.
References L P, ,,,I, RE.
Murphi
lisesand pra,puets,
EA. Genetic, and I Am Cell Cat,liul
eeercnaal hcan decn,c
pwrpcc-
1989 :11 :1458-68,
Filggins ITT. The epidemialogy of . ..genital heap disease . I Ch- Dv PMS .ig :6Y9-7'_t . 3. MuKuxck VA . hlendelirn Inheritance in hl:n. 9th ed . Baltimore. John, Hopkins Cnirersity Press . 1990. a. %I-,,-h, EA. Chore GA . Principle, 4G,-,v Counseling . Chicago: Year uses Medical . 1975. 5. Nar JJ . Nura AS . Gencuc epidemiolugy pf congenital heart disease . In: '.
Slemherg Mi . Beam AG . hlomlsky AG . Chitds
B. ads .
Progress in Iluman
Geneuc,. Philadelphia: w'B Saunders. 1983 :5.91-137, 6.
Sarchet .Cawo, A . The recurrence risk in ceegerinn! hear, disea't . Ear J
Cardiol 1978:7 .197-210 . 7 . Clark Ell . Mocha
in the pathogenesis of congenital cardiac matron
matrons . In Pierpuint MEM . Mutter JH . ed, . Genetics orCardioeascu!ar Coarse . Burners Mmhinro Niihuff . I9a1:3-12.
Pregnancy and Congenital Heart Disease JOSEPH K . PERLOFF . MD. FACC
The overall prevalence of pregnancies complicated by cardiac disease has decreasr'd somewhat during the last several decades in North America and Western Europe . but the principal change has been less a difference in prevalence than a change in the relative incidence of the various types of cardiac disorders in pregnant women (I) . Congenital heart disease is encountered more often . whereas the frequency of rheumatic heart disease has declined 1'_I . Survival into adulthood of women with congenital malformations of the heart and circulation results from natural selection or from the benefits of operation . Reparative surgery not only increases the life spun of women with anomalies that have inherent tendencies for
long survival, but also permits an increasing number of women with disorders that were previously fatal in early life to reach reproductive age (3). Central to this topic is the intricate interplay between maternal circulatory and respiratory physiology and maternal congenital heart disease . and the cfl'ccis of this interplay on the fetus that is exposed both to immediate risks that threaten its viability and to reroute risks than express themselves as developmental defects or iransntiued congenital anomalies (3) . An understanding of the relation Setween heart disease and pregnancy presupposes knowledge of the maternal circulatory and respiratory adaptations to the normal gravid state.
JACC Vol . 18, Na 2 Annu al 1991911-42
c'H 1 .11 INI H10, 1, I NiIIJCARDITiS
Prevention of infective endocarditis . Good daily oral byglene is emphasized. Foods that induce caries should be minimized or avoided . The teeth should be cared for by twice daily brushing with a soft bridle toothbrush and regular gum stimulation and flossing . k dentist or hygienist should be seen twice yearly . It is believed that fluoridatica of drinking water plays a favorable rob; . and daily "gingival degerming" with certain mouthwashes or hydrogen peroxide may decrease plaque formation and gingivitis . Meticulous skin care is also to be emphasized . Patients should meticulously avoid squeezing pimples or pusruivs and should desist from nail biting or picking with the accompanying risk of paronychiu and periungual infection . Prophylactic advice best begins in childhood to instill good habits . Chemopnphvlaris requires direct medical intervention and advice . To be successful, recommendations must he not only bacteriologically effective. but also acceptable to the patient and physician in terms of cost . case of administration haute and duration) and few if any side effects . A complex, costly and painful regimen . no natter how ellective, results in lack of compliance and no protection . The selection of an antimicrobial agent for prophylaxis is based on anticipation of which organisms are likely to be confronted and on the desirability of bactericidal activity. In patients at highest risk of infective endocarditis (those with a prosthetic device, a surgically created systemic to pulmonary artery shunts or previously documented infective endocarditis )especially recurrent endocarditis)), parenteral regimens have been advised . However, risk categories have been rendered less important with the current recommendation of oral amoxicillin for dental and upper respiratory procedures (12 .13) . Oral amoxicillin is absorbed better than is penicillin V from the gastrointestinal tract, with higher and more sustained serum levels. For most patients in whom oral penicillin V was previously recommended, that choice remains acceptable 1131 . In patients with penicillin allergy . use of erythromycin, especially erythromycin cthylsuccinale and stcaratC,
is giving way to use of oral clirdamycin. Details retarding the preceding recommendations are available in the current American Heart Association statement 1121 on prevention of bacterial endocarditis and antiinfective endocarditis prophylaxis .
References I.
Karl.. EL, Riuh H. Gersony W, Manning J .
,,,Deco
alluburutwe study of
enducnd,i, .mihe197w.emiAn,
u rpetlrnts .hu
have undergone cardiovascular surgery. Cheat, ,,o 1979.59:3 17-35, '- . DecIber D, Iksbs LL . Chakem S. Fullol's
leis
logy
n 20
year surgical
ioiluw-up, Br Heart 1 1971 :}1 :t2 12 . 3 [maciho JS . Belcher P. Knight Wit. Infecuon of modified Bialnek shams . Br Heat J 1987 .58 :287-90, 4.
Johnson DH . Rosenthal A . Nadas AS . A funs year review of bacnrial
rnd,xard,i, in infancy and sh,Whad . Circulation 1975:57 :581-8. 5, John- CM . Rhodes KH . Pediatric endaardai •. Mayas Clin Pros 1982 : 57:86-94 . 6 . Kaplan EL Infertive enda.arduts in the pediatric age group . An over-- . In: Kaplan EL . Tannin AV . ads . Inteavve Fndocarditis. An American Hero Association Symposium . Dallas . TX : Amennan Hean Asacialiml. 1977 :$1-4 .
7 . Gersuny WM . Have, CJ . Bacterial endoearditis in patients with pulmonary sIeno,i, . anti[ sIcno,is or venMcular septa) defect . Circulation 1977.S61sappl 11 :1",'d_7. 0. Everest ED. Hirschmann IV . Transient bacteremia and endocarditis prupht,!anis: a nview. Medicine 1977 :56:61-77. 9. Corgi, G . Erbcl R . Hennahs KS. Wenchel H.M . Worst H-P. Meter J . Posaive blood cultures during Iansesophageal echocardiography . Am J Cardiol 1998:65:1404-5. 10. Chandraseken K . uansal RC . Mints 4S . Ross 1J . Shah PM . Impact of hansesophageal color flow Doppler echocardiography in current clinical practice . Echocardiography 1990 :7 :115-45 . If. Foster E. Kusumata FM . Sobol SM . Schiller NB. Streptococcal endocarditis temporally related to tmnaesopheural echavardio
vphy,
l Am
San Echo 1990:5 :424-7 . C . Daaani AS. Barn AL, Chung KJ. el al. Prevention of bacterial andocarth . tis, recommendations by the American Heart Association . JAMA 1990: 264:2919-222 . 13 . Endoearditis Warkitg Party of the Banish Society for A ;.:isrimubial ehemomerapy. Anhhintie prophylaan of mieettve crdaardin . I_ao-c, 1990:31:88-9.
Assessment of Genetic Risk in Congenital Heart Disease EDMOND A . MURPHY, MU . REED E, PYER:-IZ, MU . PHU
Most studies an the genetics of congenital heart diseases have devoted much effort to traditional questions . questions that are often not central to the issue . There has been little attention to defining and exploring the fundamental problems to which coherent inquiry can be directed . After long inaction, interest in the genetics of congenital heart disease is slowly reviving. The approaches are on several quite dif-
ferent fronts: cytogenetic, hinchemical, analytic, statistical, mathematical and clinical. Though quite diverse and nut easily unified, they are by no means irreconcilable . The prospects are promising, exciting, even revolutionary ; but at this stage, the knowledge is germinal only and not ready for clinical application. We (1) recently reviewed some of this knowledge .
JACC Vol . 18. Na . 2 Aaron ts'1O11-i?
MURPHY AND PYERITZ AsSESSSte,uT tie GENETIC RISK IN CONGENITAL . HEART DISEASE
The key questions, however . may seem bizarre To the clinician. This brief report is no place to expound these leads . Our concern here is much more practical . We stress, again that what follows is tentative : at best provisional in matters of fact and even in its broad relation to what the final solutions may he .
Etiology and Pathogenesis the best and most useful statements about risk depend an .he resolving power of the data and on the part that explicit and formal reasoning is allowed to play in the analysis . An excellent example of the noncommittal approach is that of Higgins . (2} At one extreme, the usual method of epidemiology makes little attemp[ at actual rational understanding . The classic example, congenital heart disease due to maternal rubella- was well established in the firs) place on purely empire grounds. It was only when the relation was shown that the pathogenesis was explored. For the most par' . epidemiology pays little attention to basic mechanisms- Any deeper understanding and any more precise assessment of risk call for some degree of modefiny . that is, same cunjeclore about how the process operates . In some aspects of genetics. there are unusually persuasive grounds for such . The models : in others, the grounds are more conjectural current primitive understanding o'i the etiology of mast forms of congenital heart disease re',lects the gross neglect of modeling. We know of many genetic types of congenital heart disease . some Mendelian . some chromosomal . sonic perhaps cytoplasmic . some chemical : we know of several cnvirunmental factors (infections such as rubella and cytomegalovims: intoxication inch as ethanol and vitamins ; metab!ic factors such as maternal diahetesl . But few of them lead to precise and secure assessments of risk, the main reason is That nothing isknuwn of pathoger'esu . 11 dvCs little good to patch up disparities in the data by vague notions I"variable expressivity ." 'incomplete penetrance ."multifactorial inheritance." "interaction' 'I . patches that are lacking it.. precisely defined properties that can pe investigated cogently, falsified . verified and authenticated At the present time, the clinical cardiologist must be content to keep track of a few proved risk factors- The means of predicting the -mhined effect of cnnirunmental and genetic risks are exquisitely precise in the hemolytic anemia favism for the very reason that the pathogenesis Is well understood . However, in congenital heart disease . pathogenetic insights will not be available in the foreseeable future : when they arrive . they may have startling properties .
Practical Assessment of Risk This topic . the gist of our discussion . will reflect these notions of degree of explicitness, The field is controversi :d and it is best to confine ourselves to what is agreed on among reputable authorities .
339
Mendetiziug trails. Quite a formidable list (3) can be compiled of congenital heart disease that seems to be inherited as Mendelian (single-gene) trails. sonic of them defects of structure (like the Holt .Uram syndrome), some of tissue (like Marfan's syndrome( and some of function (like the Jerveli-Lunge-Niclsen syndrome of QT Interval prolongalion . ventricular tachy'cardia and deafness) . The family Patterns are often irregular . perhaps because the phenotype is uncomfortably far removed from the gene action . More systematic collection of data and more sophisticated attention to minor changes in "unaffected" relatives would doubtless improve the underctauding ol'the pattern and the prediction of recurrence risks . 'I he advantage of Mcndelfan traits is that the rules for genetic counseling can be svgternatically (though not trivially) derived from Mende:inn >trinciples (4) . However . Mendclian congenital hear[ disease, though in aggregate perhaps not uncommon, is individually rare . Chromosome abnormarilies. Congenital heart disease may occur as a feature of chromosomal anomalies (the syndromes of TerOCr and Down . lrisomy-13) . The occurrences of congenitzi Sean disease are irregular, and at present there are theories but no accepted explanations for them . The most cie can say is that the occurrence of these disorders should alert the clinician to the possibilities of the cardiac lesions . Specific fawfty recurrence. The theory of thresholds (4) suppose, that the phenotype for congenital heart disease is or is not present depending or whether the value of some hypothetic quantitative [rail e .tceeds a threshold. The fact that the probsnd is affected and therefore has exceeded this threshold makes it Inure likely that any close relative will also exceed it. This model in congenital heart disease has been explored largely by Nora and Nora0) and by SanchezCascos to with considerable success . go[ the proper use of the full theory in genetic c ounseling . i s not only complex but tedious and no Clinician has satisfactorily applied it in pedigrees with multiple affected siblings- Moreover- there has been little concern on the part of either clinicians or theorists in pursuing the implications of the hypothetic quantitative trail. The one useful working principle front it is that under usual circumstancesm the average number of abectcd first-degree rclativex is prnpnnional to the square root of the frequency of the trait in the population at large. Thusa if a trait has a frequency of I in 10.0110 . the expected proportion would be I in IOo or I (note that 1%. is a proportion : it is not the probability of recurrence . which in any particular family increases with the number of affected relatives) . Nonspecific ramify recurrence risk . Many studies analyzing the "black box" recurrence risks in relatives according to the types of lesion in the prohand show that the cardiac phenotypes do not breed true . Relatives of a patient with defect A are themselves at higher risk than average of having defect A : they are also at somewhat higher risk of having other lesions (B and C . and so forth) . We may couple this
3411
P1 Ri (* 1 I'CI ( ;N%,%('1' ANO ('ONGIfNil ' :1L HLAk'I I715F`ASi' .
lack of specificity with the diversified )" plciotropic') characier of cantenlial heart diseases, even those hat seem to be Mendelian . 'Iogetiler they have given rise to the notions that ,hat is inherited is not unr~p4++fogir but uu+rppugeu'tir . The geneticist should he looking for unifying defects of develop . mental mechtmisms . not unity in their effects . ']'he risks of recurrence may be compared with the 5117r for dominant genes and 257 for recessive genes . The in . crease in risk for non-Mendelian traits is then small . One would have expected as much, fur a high recurrence risk (such as occurs in the simple Mendelixing cases) takes a heavy selective loll, so that the traits should remain rare . (To the clinician . congenital heart disease may appear to he rare . but among genetic diseases it is astonishingly common) . Massive empiric evidence confirms the predicted low recurrence risk- The average recurrence risk in congenital heart disease is usually not = J7r to 597 . the kind of risk figure one uses in counseling when all else fails . Needless to say . wherever an adequate history would furnish a more rational basis for calculating risk (lot' instance for the Jcrvell-LangeNielsen syndrome which is autosomal recessive). one would use that risk. Semispecific family recurrence risk . Between the extreme rigorof the Mendelian analysis and the nihilism of pure black box risk, there is a type of analysis that is growing in popularity. It is based on the notion [hat certain groups of lesions may occur together more often [ban others because they are more closely related in etiology and pathogenesis . such as hemodynamics or contributions from the neural crest . The classification of congenital heart disease by Clark (7) is an attempt at such a rational ordering . One instance for which there is now excellent evidence is defects of the left
tArc V.,) Is. No .2 Augurs -1111-42
ventricular outflow tract . Too narrow a concern with anatomic specificity would obscure this valuable c lue . a s would too indiscriminate a pooling of data. The relation can be usefully if tentatively interpreted as the result of common hydraulic factors at work . Conclusion Most of our useful common knowledge about the genetics
of congenital pearl disease appeals to a few rational principies, which may be somewhat refined by better phenotyping, linkage analysis and exploration of candidate genes . All the current indications are that the major advances in this field in the next 10 years will come from a deeper understanding of pathogenesis and the accurate measurement of the effects of morphogenetic genes.
References L P, ,,,I, RE.
Murphi
lisesand pra,puets,
EA. Genetic, and I Am Cell Cat,liul
eeercnaal hcan decn,c
pwrpcc-
1989 :11 :1458-68,
Filggins ITT. The epidemialogy of . ..genital heap disease . I Ch- Dv PMS .ig :6Y9-7'_t . 3. MuKuxck VA . hlendelirn Inheritance in hl:n. 9th ed . Baltimore. John, Hopkins Cnirersity Press . 1990. a. %I-,,-h, EA. Chore GA . Principle, 4G,-,v Counseling . Chicago: Year uses Medical . 1975. 5. Nar JJ . Nura AS . Gencuc epidemiolugy pf congenital heart disease . In: '.
Slemherg Mi . Beam AG . hlomlsky AG . Chitds
B. ads .
Progress in Iluman
Geneuc,. Philadelphia: w'B Saunders. 1983 :5.91-137, 6.
Sarchet .Cawo, A . The recurrence risk in ceegerinn! hear, disea't . Ear J
Cardiol 1978:7 .197-210 . 7 . Clark Ell . Mocha
in the pathogenesis of congenital cardiac matron
matrons . In Pierpuint MEM . Mutter JH . ed, . Genetics orCardioeascu!ar Coarse . Burners Mmhinro Niihuff . I9a1:3-12.
Pregnancy and Congenital Heart Disease JOSEPH K . PERLOFF . MD. FACC
The overall prevalence of pregnancies complicated by cardiac disease has decreasr'd somewhat during the last several decades in North America and Western Europe . but the principal change has been less a difference in prevalence than a change in the relative incidence of the various types of cardiac disorders in pregnant women (I) . Congenital heart disease is encountered more often . whereas the frequency of rheumatic heart disease has declined 1'_I . Survival into adulthood of women with congenital malformations of the heart and circulation results from natural selection or from the benefits of operation . Reparative surgery not only increases the life spun of women with anomalies that have inherent tendencies for
long survival, but also permits an increasing number of women with disorders that were previously fatal in early life to reach reproductive age (3). Central to this topic is the intricate interplay between maternal circulatory and respiratory physiology and maternal congenital heart disease . and the cfl'ccis of this interplay on the fetus that is exposed both to immediate risks that threaten its viability and to reroute risks than express themselves as developmental defects or iransntiued congenital anomalies (3) . An understanding of the relation Setween heart disease and pregnancy presupposes knowledge of the maternal circulatory and respiratory adaptations to the normal gravid state.
