Prevalence of significant congenital heart defects in children of parents with Fallot's tetralogy

will not be like that of digitalis or a diuretic or other conventional drugs for cardiomyopathy. Over 30 years of biochemical research on CoQlo have revealed that its clinical effectiveness requires the presence of specific apoenzymes, which are proteins with receptors for CoQlo. The fact that 71% of the patients in this study responded in 3 months is presently understood to be based on the time-requiring mechanisms for the biosynthesis of the apoenzymes from DNA and then RNA. The fact that 16% of the patients responded in 6 months may reflect that the lOO-mg dosage was too low or that other deficiencies in these patients slowed the therapeutic response to CoQ,o. The clinical response to CoQl~ over monthly periods is acceptable in biochemistry for a vitamin in contrast to the almost immediate clinical responses of drugs that act by pharmacologic mechanisms. CoQlo has been demonstrated to be effective and safe for the treatment of patients with dilated cardiomyopathy over a period of 6 years. The thesis that deficiencies in intracellular bioenergetics might be a factor in myocardial failure is strongly supported by these results. Further study could possibly have a major positive impact on myocardial failure from all causes. 1. Langsjoen PH, Vadhanavikit S, Folkers K. Response of patients in classes 111 and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Qlo. Proc Nat1 Acad Sri USA 1985;82:4240-4244. 2. Mortensen SA, Bouchelouche E, Muratsu K, Folkers K. Clinical decline and

Prevalence of Parents Thomas

of Significant with Fallot%

Congenital Tetralogy

relapse of cardiac patient on coenzyme QIo withdrawal. Biomedical and Clinical Aspects of Coenzyme Q. New York: Else&r Science Publishers, 1986:5:281290. 3. Vadhanavikit S, Sadahoto N, Ashida N, Kishi T, Folkers K. Quantitative determination of cocnzyme Qlo in human blood for clinical studies. Anal Biochem 1984:142:155-158. 4. Weissler AM, Harris LC, White CD. Left ventricular ejection time index in man. J Appl Physiol 1963;18:9/9-923. 5. The Concensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;3/6:1428-1434. 6. Bairn DS, Colucci WS, Monrad ES, Smith HS. Wright RF, Lanoue AS, Ransil BJ, Grossman W, Braunwald E. Survival of congestive heart failure patients treated with oral milronone. JACC /985;5:44/. 7. Unverferth DV. Magorien RD. Moeschberger ML, Baker PB, Fetters JK, Leier CV. Am J Cardiol 1984:54:147-152. 8. Cohn JN, Levine B, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819~823. 9. Franciosa JA, Wilen M, Ziesche S, Cohn JN. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983;51:831-836. 10. Creager MA, Faxon DP, Halperin JL, Melidossian CD, McCabe CH, Schieck EC, Ryan TJ. Determinants of clinical response and survival in patients with congestive heart failure treated with captopril. Am Heart J /982;/04:1147m 1154. 11. Massie B, Ports T, Chatterjee K, Parmley W. Ostland J, O’Young J. Haughom F. Long-term vasodilator therapy for heart failure: clinical response and its relationship to hemodynamic measurements. Circulation /98/,63:269278. 12. Wilson JR. Schwartz JS, Sutton MS, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. JACC 1983;2:403-409. 13. Walsh WF, Greenberg BH. Results of long-term vascdilator therapy in patients with refractory congestive heart failure. Circularion /981,64:499-505. 14. Kereiakes D, Chatterjee K. Parmley WW, Atherton B, Curran D, Kereiakes A, Spangenberg R. Intravenous and oral MCL 17043 (a new inotrope vasodilator agent) in congestive heart failure: hemodynamic and clinical evaluation in 38 patients. JACC 1984;4:884-889.

Heart

Defects

in Children

M. Zellers, MD, David J. Driscoll, MD, and Virginia V. Michels, MD

here is a paucity of empiric recurrence risk data T for children of patients with some forms of congenital heart defects, especially cyanotic forms such as Fallot’s tetralogy (TF). This information is necessary for accurate genetic counseling because many of these patients now reach reproductive age and wish to know the From the Section of Pediatric Cardiology and the Department of Medical Genetics, Mayo Clinic and Mayo Foundation, 200 First Street SW,

Rochester, Minnesota 55905. Manuscript received August revised manuscript received and accepted October 10, 1989.

8, 1989;

risk to their children. This investigation estimates the prevalence of significant congenital heart defects (i.e., those brought to the attention of a medical provider) in children of parents with TF. Questionnairesweresentto 395patients with TF who wereevaluated at our institution between1945 and 1968 (Figure 1). Thesequestionnairesaddressedthe presence or absenceof congenital heart defects in children and other first-degree relatives of, as well aspregnancy and miscarriage rates in patients with TF. Thesepatients

395 patients with Fallot’s tetralogy (1945-68) Questionrlaires sent FIGURE 1. Fbw diagram lkmimting quedhdm.prucess d respome rate toquedmme.F=female;M=mak.

I 18 died

228 returned questionnaires

142 unblaimed questionnaires

7 refused participation

I

34 married No children

127 (62 F:65 M) Married with children

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TABLE I Children of Parents with Fallot’s Tetralogy Families No. Children/Family

No.

%

1 2 3 4 5 6 Totql

44 54 21 4 2 2 127

34.6 42.5 16.5 3.2 1.6 1.6 100

were chosen because they were I1 8 years of age. From previous use of questionnaires regarding prevalence of congenital heart defects in siblings and offspring, it is known that subjects tend to overestimate the prevalence, frequently considering “innocent murmurs” to represent congenital heart defects. To avoid this overestimation, very specific questions about the “murmurs” were designed to obviate this problem. The familyphysician or thepediatric cardiologist who evaluated the child was contacted only ifthe responses were still ambiguous. Of the 395 questionnaires mailed, 228 (588%) were returned completed. One hundred forty-one (36%) were returned unclaimed and 7 (2%) subjects refused to par-

ticipate. Eighteen of these patients died, 3 after having 5 reportedly healthy children. These children were excluded because of a lack of detailed information. The mean age of theprobands at the time of this questionnaire was 38 f 10 years (range 24 to 78). One hundred sixty-one of the 228 (71%) subjects were married and of these, 127 (79%) had 1 or more children. No unmarried subjects reported having any children. Of those who were married, 86 were men and 75 were women; no subject had a spouse with a congenital heart defect. Of the 86 married men, 65 (76%) had 148 children and 62 (83%) of the 75 married women had 105 children (Figure 1). The number of children per family is listed in Table I. Twenty of the 62 married women had a combined total of 28 abortions. Twenty-five of these were spontaneous and 3 were therapeutic cfor maternal health reasons), for a miscarriage rate of 19.2%, which is within the previously reported range of miscarriage rates for a general population.‘s2 Congenital heart defects occurred in 3 (1.2%) of the 253 children: all 3 were girls, 2 of whom had affected fathers and 1, an affected mother. The lesions in the 3 children were truncus arteriosus (l), ventricular septal defect (1) and TF (1) (Figure 2). All lesions were conj?rmed by a pediatric cardiologist. The children with TF

127 parents I 65 !nen

62 w&en

I 146 children

I 105 children 104 -NL

1 TOF

1 VSD 46NL 1 truncus

1.5% (CL = 0.16-4.73)

0.93% (CL = 0.02-5.19)

FIGURE 2. Fbw diagram ihstraling numberofchlldmwlth/wRhoul~ headrliruuofmalsandfemalepathte with Fdot’s tetralogy. CL = coddemw llmltqNL=nonnd;TGF=telralogyof Fdkt;bun#a=-artariorur;VsD =vanbiculr~defSCl.

Total: 1.2% (CL = 0.25-3.47)

FIGURE 3. Prevalence of cmgembl d8fSCtSillChikbWlOfpranbwlthFaWOt’S tetr~frommwentsMYuld4other

oftotai-rtudkd.Bafs=93%confldence Pmib (CL).

0

0 Zellers, 1989

524

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Ando. 1977

head

TABLE

II Recurrence

Risk of Congenital

Heart CHD

Proband Gender

Defects

for Children

of Patients

M Probands F

CHD/Total

%

CHD/Total

Dennis & Warren3 Singh et al4 Ando et aI5 Nora & Nora Present study Total

36

2

3/71 -

4.2

65

62

1.3 2.3

2/14a 4/219

M plus F

F Probands

M

heart detect; CL = confidence

Tetralogy

in Offspring

Study

CHD = congenital

with Fallot’s

%

CHD/Total

%

o/47

0

l/105 l/152

0.9 0.66

3/118 l/N l/12 6/141 3/253 14/554

2.5 3.3 8.3 4.2 1.2 2.5

CL 0.52-7.13 O.ml7.22 0.21-38.48 1.57-9.15 0.253.47

limits.

and truncus arteriosus also had autopsy confirmation of their lesion. The child with the ventricular septal defect had experienced spontaneous closure of her defect. There was no apparent relation between the occurrence of congenital heart defects in offspring and the number of offspring per parent or the birth order of the offspring. The prevalence of congenital heart defects in the siblings and parents of the subjects questioned was 2.3 and 0.43%, respectively. The prevalence in siblings of male and female parents was similar. Only 1 grandparent had a Congenital heart defect (patent ductus arteriosus).. The recurrence risk of a congenital heart defect for children of a parent with TF has been reported to be 2.5 to 8.3% (Table II, Figure 3).3-7 In our study, the largest reported thus far, the recurrence risk of significant congenital heart defects in children is 1.2% and is comparable to that previously reported. Two of the 3 patients with congenital heart defects had conotmncal abnormalities. The recurrence risk in siblings of patients with TF has been assessedby several investigators3~5~8-10and found to be consistent with the multifactorial mode of inheritance, with a recurrence risk of 2%. In the present study, the recurrence risk was 2.3% for siblings of probands, similar to that reported by other investigators (Table III). This suggests that our ascertainment of affected relatives is !3~* The reasons for these discrepancies in recurrence risks in children born to parents with congenital heart defects in our study and the risks quoted in those studies by Whittemore,” Rose,‘* Emmanueli and their associates are unclear. Ascertainment bias, local environmental factors and chance are possible reasons for this. For example, in Whittemore’s prospective study, it is possible that patients invited to participate who already had several healthy children may have declined participation. In the retrospective studies, many patients were not located; it may be more likely that patients with affected children would remain in contact with the medical center. Filly, the studies by Whittemore,il Rose I2 Emmanuel13 and their associates did not specifically address recurrence risk in children of patients with TF. A potential weakness in the study design of this investigation is that the children were not examined by the investigators. This could result in an underestimation of recurrence risk, especially for subtle lesions such as bicuspid aortic valve. However, all children were examined by their own pediatrician and many have been examined by

TABLE Ill Recurrence Siblings

of Subjects

Risk of Congenital with Fallot’s Tetralogy

Heart Siblings

Authors

Probands

Siblings Total No.

Boon et al8 Ando et al5 San&ez-Cascosg Dennis & Warren3 Nora 81 Noral Present study Total

100 1% 113 61 157 228 855

189 380 327 100 338 567 1,901

Abtww

Defects

for

with CHD

No.

%

CL

4 6 4 0 9 13 36

2.1 1.6 1.2 0 2.7 2.3 1.9

0.58-5.3 d.54-3.26 0.36-3.38 O-3.62 1.12-4.95 1.15-3.69

as in Table IL J

pediatric cardiologists (especially if they had cardiac murmurs). It is unlikely that signilicant cardiac abnormalities would have been overlooked. Also, it has been demonstrated in a large cohort study14 that 88% of congenital heart defects are diagnosed by 1 year of age and 98% are diagnosed by 5 years of age. Only 5.5% of the children from this study were younger than 1 year. To prevent overdiagnosis by inclusion of patients with innocent or functional murmurs,*5 very specific questions relating to these murmurs were included in the questionnaire. Cardiologists evaluating these murmurs also were contacted when, despite these questions, ambiguity still existed. All suspected innocent murmurs were confiied to be innocent by these physicians. Thus, we think overdiagnosis is unlikely. These data are similar to previous reports of recurrence rate of congenital heart defects in children of parents with TF and represent the largest study of parents with TF. This information will be useful for counseling patients with TF regarding their risk for having a liveborn child with a significant congenital heart defect. 1. Warburton D, Fraser FC. Spontaneous abortion risks in man: data from reproductive histories c&xted in a medical genetics unit. Am J Hum Getter 1%4;16:1-25. 2. Bierman JM, Siegel E, French FE, Simonian K. Analysis of the outcome of all pregnancies in a community, Kauai pregnancy study. Am J Obstet GyneeOr 1%5,91:37-45. 3. Dennis NR, Warren J. Risks to the offspring of patients with some common congenital heart defects. J Med Gem? 1981;18:8-16. 4. Singh H, Bolton PJ, Oakley CM. Pregnancy after surgical correction of tetralogy of FaUot. Br Med J 1982;285:16&170. 5. Ando M, Takao A, Mori K. Genetic and environmental factors in congenital heart disease. In: Inouye E, Nishimura H, eds. Gene-Environment Interaction in Common Diseases. Baltimore: University Park Press. 1977:71-88. 6. Nora JJ, Nora AH. Recurrence risks in children having one parent with

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congenital heart disease. Circulation 1976;53:701-702. 7. Bum J. The aetiology of congenital heart dii. In: Anderson RH, M&artney FJ, Shineboome EA. Tynan M, eds. Paediitric Cardiology. Vol. 1. New York Churchill

Livingstone,

1987:1563.

8. Boon AR, Farmer MB, Roberts DF. A family study of Fallot’s tetralogy. I Med

&net

1972,9:179-192.

9. Sanchez-Cascm Cardiol

A. The rccwrence

risk in congenital heart disease. Eur J

1978;7:197-210.

10. Nora JJ, Nora AH. Genetics and environmental factors in the etiology of congenital heart disease. South Med / 1976.69.919-926. 11. Whittemore R, Hobbii JC, E&e MA. Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. Am J Cardiol

Depressed Left Ventricular Richard T. Lee, MD, Maureen Plappert,

CVT, and Martin

normal systolic performance has been demonstrated in humans with severe, primary hypothyroidism; replace ment of thyroid hormone leads to normalization of systolic time intervals in these patients3 Recently, a new Dopp ler method of noninvasively determining left ventricular (LV) ejection force was described.4 Using Newton’s seu ond law of motion, force may be derived from the product of the mass and acceleration of blood ejected out the aortic valve. This study tests the hypothesis that this new noninvasive method can detect subtle changes in LV systolic function in patients with primary hypothyroidism. From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Harvard Medical School, Boston, Massachusetts 02115. Dr. Lee. is a recipient of Physician Scientist Award HL-01835 from the National Institutes of Health, Bethesda, Maryland. Manuscript received September 11. 1989: revised manuscript received and accepted October 23,1989.

40~ G f, sw 3 ILb

f

20--

f A A

lO--

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12. Rose V, Gold RJM, Lindsay G, Allen M. A possible increase in the incidence of congenital heart defects among the offspring of affected parents. JACC 1985,6:376-382. 13. Emmanuel R, Somerville J, inns A, Withers R. Evidence of congenital heart disease in the offspring of parents with atrioventricular defects. Br Heart J 1983;49:144-147. 14. Hoffman JIE, Christianson R. Congenital heart disease in a cohort of 19.502 births with long-term follow-up. Am .I Cardiol 1978;42:641647. 15. Czeizel A, Pomoi A, Piterffy E, Tarcal E. Study of children of Parents operated on for congenital cardiovascular malformations. Br Heart J f982;47: 290-293.

Systolic Ejection Force in Hypothyroidism

xperimental hypothyroidism is associated with E depressed myocardial contractile function, possibly due to alterations in contractile protein isoforms.1~2 Ab-

30--

1982;50.641-651.

VOLUME

65

G. St. John Sutton, MRCP

Twelve outpatients (11 women and 1 man) with newly diagnosed idiopathic hypothyroidism were studied. The ages of thepatients rangedfrom 35 to 68 years. The diagnosis of hypothyroidism was based on typical clinical symptoms (as determined by the patient’s internist) and a thyrotropin level >I5 nU/ml. Patients with histories of cerebrovascular or cardiovascular disease were excluded. No patient was taking diuretics, antiarrhythmic agents, vasodilators or other cardiovascular medications. A Hewlett Packard 77020 AC/AR ultrasonoscope dwice with a 2.5~MHz transducer was usedfor all studies. Pulsed-wave Doppler sampling of the LV outjlow tract was performed in the apical j-chamber view with the sample volume located just beneath the aortic valve leaflets. Doppler echocardiographic studies were repeated after thyroid replacement in 8 patients. Patients were considered to be euthyroid if their clinical symptoms resolved and serum thyrotropin hadfallen to <7 nU/ml. The mean time of treatment to establish euthyroidism was 23 weeks; follow-up echocardiograms were performed <3 weeks after the demonstration of euthyroidism. Echocardiographic data were analyzed using a Cardiology Workstation (GTI Freeland Medical Division). LV mass, volumes and ejection fraction were calculated as previously described5 Systolic force was determined as prwiously described.4 Systolic force values from the patients were compared to those of I2 normal volunteers with no history of cardiovascular or thyroid disease. The 2-sample Student t test was used to compare patients with normal subjects and the paired Student t test was used to analyze the effects of thyroid replacement; a p value X0.05 was considered to be statistically signi!cant. All patients and normal volunteers had normal echocardiograms except 1 patient who had a trivial per&rdial effwion that resolved after thyroid therapy. There were no signijicant differences in heart rate, end-systolic or end-diastolic volume index, ejection fraction or systolic blood pressure after thyroid replacement (Table I). There was a small but signijicant increase in diastolic blood pressure after thyroid replacement. The systolic force in normal volunteers was 23 f 4 kdym. In patients with hypothyroidism, systolic force was markedly abnormal before thyroid replacement