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5e6 ..,, ~~:-- ~tl`~t'al•~~~ Lipoprotein and Oxygen Transport Alterations in Passive Smoking Preadolescent Children The MCV Twin Study W'illlam B. Moskowitz. MD. Michael' Mosteller. PhD; Richard M. Schieken. MD, Rodrigo Bossano, MD, John~ K. Hewitt. PhD. Joann N. Bodurtha, MD, MPH, and Jere P. Segrest, MD. PhD We investigated the cardiovascular effects of lifelong passive cigarette smoke exposure in preadolescent children and examined the following questions: 1) Is systemic oxygen transport altered? 21 Are coronary heart disease risk factors adversely affected? We recruited 216 families from the MC'V Twin Study; 105 had at least one smoking parent. Serum thiocranate and cotinine levels were used as measures of smoke exposure in the children and thiocyanate was proportional to the number of parental cigarettes smoked each dav (p=0.0001). Paternal smoking had no effect on these measures. Whole blood 2,3-dipbospboqlycerate was higher in smoke-exposed than unexposed children (p<0.01) and was related to the thiocyanate level (p<0.02)~ High density lipoprotein (HDL)'cbolesterol was lower in passive smoking children ( p<0.051G the HDL; subtraction was reduced in passive smoking bvys, while the HD~L, subtraction was reduced in passive smoking girls. Significant adverse alterations in systemic oxygen transport and lipoprotein profiles are already present in preadolescent children exposed to long-term passive cigarette smoke, primarily from materaal smoke. Chuldren with long-term exposure to passive smoke may be at elevated risk for the development of premature coronary beart disease. (Circu(arion 1990;81:586-592) T /r"rlhe adverse health effects of actively inhaled ~ cigarette smoke include impaired pulmonarv iun<<c~ic~n. increased'coronary and cerebrovas- cular disease, chronic pulmonary disease, and canccr.1-}'Ci¢arette smoking is a powerful indepen- dent risk factor for myocardial infarction, sudden death, peripheral vascular disease, and'stroke an6 is the most important of tttt modifiable risk factors for coronary heart discase.• 1be greatest relative risk related to smoking occurs in younger age groups.5 land an unusually liigh proportion of individ'uals with premature coronary heart disease are smokers.b Therefore. smoking is an important risk factor asso- ciated with premature coronary heart disease.. From the Children s Medical Center. Dtwston of Pediatnc Cardiologv. the Department of Human Genetics of' the Medical College of Virginia. and the Ltpoprotun Laboratory. Umversrtyof Alabama h4edical Center. Supported hy the National Institutes of Health. National Heart. Lung. and Blood Institute f R29 HL•38878 and RO11 HL•31o101:. Address for conrespondence. William B. MoskoWitz MD. P.O Box 5a3 MCV Stauon. Richmond. VA 23298-05t3 Received August 8. 1988, revtston aceepted Oaober 13. 1989. Infanu and young children of smoking parents who are passively exposed to cigarette smoke are more at risk for lower respiratory tract infections and smalli airwav disease than are children of nonsmoking parents.'-$ What is less clear is whether the cardio- vascular and oxygen transport systems of the growing chil6l arc adversely affecte& by long-term exposure to passive inhalation of cigarette smoke. Atheroscl'c- rotic changes found'in'mid'dle-agcd'men may begin in childhoo6 where certam risk factors are thought to be related to the earliest stages of atherosclerotic disease.9•10' Therefore. we asked the following ques- tions: 1) Is systemic oxygen transport altered in chronically exposed passive smoking children of active smoking parents? 2) If abnormalities cxist, are they related to the amount of cigarette smoke expo> sure? 3)~ Does passive cigarette smoking in~ preado- leseent children~ detrimentally alter their coronan• hean disease nsk factors' To answer these questions. we evaluated the systemic oxygen transportvariables. coronary risk factors, and echocardiographic cardio- vaseul'ar measurements of 216 pairs of preadolescent twins from smoking versus nonsmoking families.

.WYoskowtc er a! Passive Smoking Effects in Children f I Methods Populatton As pan of'an ongoing genetic longitudinal~studv of~ developmental changes in cardiovascular risk factors durtng adolescence, we recruited families with twins from nearbv school systems. Eleven-year-old twins were ascertained' from more than 75 middle schools of central VirQinia: within a 150-mile radius with use of a computerizedi population-based registry. Infor- mation~ packets were mailed to the schools for distri- b~.non to parents of twins to maintain confidentiality from the investigators. The parents who replied by mail (50%) were invited to participate. The families participated in a protocol that included the collection of data on family health histories. smoking historv (historical data provided byy parents): blood pressure. electrocardiographic mea- surements. echocardiographic measurements. and the collection of'blood samples for biochemical assays. The number of cigarettes smoked each day by the parents was recorded. No attempt was made to prescrecn~ enrollees for the presence or absence of cardiovascular risk factors. Informe& written consent. which had been approved by the Committee on the Conduct of Human Research off the Virginia Com- monwealth Lniversity„was obtained from each~fam- ilv before it entered the study. Procedurrs Arahmpomarics and blood pressure. Height and weight of each subject in stocking feet were measured with a stadiometer and digital scale, respectively. Sexual maturation was self-assesse& by asking each subject to select a drawing of the Tanner stage of pubic hair development that most closely corre- sponded to his or her own level of sexual develbpment." Two resting blood pressure measure- ments were obtained with the subject in~ a sitting position using a mercury sphygmomanometer and the appropriatelv sized compression~ cuff. The fourth Korotkoff phase was recorded as the diastolic blood pressure. Echocardiography. Echocardiographic left ventri.c- ular wall thicknesses and chamber dimensions were measured according to stand'ardized' measurement cnteria.12 Echocardiograms were obtained with the subject in the recumbent position using an SKI ultrasonoscope 20'A with a 3.5 MHz probe an& Honeywell 1856 strip-chart recorder. Echocardio- grams were obtained and read in a blinded fashion; the individuals performing and reading the echocar- diograms were not aware of the passive smoking status of the children. The echocardiographic trac- ings were placed over a bit pad and using a micro- computer, digitized echocardiographic dimensions, wall thicknesses, and hean rate were measured and stored on diskette. The measurements were not adjusted for heart rate. The data from the diskette were transferred to a computer where the echocar- diographic-derived variables were calculated.l3 Blood samples. A sample of whole blood u as obtained. stored'on ice. and processed within 1 hourr for quantitative lipoprotein cholestcroll measure- ments using the vertical spin uftracentrifugation technique.1''Quantitative lipoprotein cholesterol le, = els were obtained on all but five nonsmoking and three passive smoking twin pairs. Hematocrit was determined in duplicate by capillary, tube centrifuga- tion. Early in the studv. we obtained the techniques to measure whole blood ttiiocvanate level (n=108 twin pairs)ian6red blood cell 2.3-diphosphoglvicerate level (?.3-DPG): (n=163 twin, pairs). Blood thio- cvanate concentration was determined by a quan- titative colorimetnc method at 450 nm'"'6 and re6cell 2.3-DPG level was determined bv the method of Fiske and SubbaRow.17 Serum cotinine concentration was quantitated by radioimmunoassay methods.1Sl9 Data ,4nalvsis Data are presented as meancSD. Statistical dif- ferences between group means were assessed by two-sided r tests, taking into account whether group variances were equal. Because twins share genes and environments and'represent nonindependent obser- vations. data from only a single twin randomly ascer- tained from each family was used to determine group means for statistical testing. Nonparametric correla- tion coefficients using the Kendall Tau B statistic were used when it was apparent that; a given vanable was not normally, distributed. such as cigarettes smoked each d'av, serum thiocvanate. and high den• sity lipoprotein (;HDL) cholesterol. Regression anaiv- sis was used~ to remove the effects of confounding variables. Group means for passive smoking and nonsmoking subjects were adjusted to~ correct for differences in age, height, weight, and, when the groups included both males and femaies, sez. A multiple linear regzes- sion analysis was conducted in~ which the response variable was modelled as a linear function of the above covariates. Regression coefficients were obtained and the expeaed' value of the response variable was cal- culated with the covariates fixed to their mean~values. These adjustment computations were carried out using the LsmEA.HS option of the General Linear Models procedure of the SAS statistical package. The hentabiliry, of specific variables was estimated as two times the difference of the twin correlations in monozygotic and dizygotic pairs.m All~ results were considered statistically significant at p<0.05. Results Smoking data were available on 216 families enrolled in the MCV Twin Studv. One hundred eleven of these families had nonsmoking parents. Of these nonsmoking families, both parents were never smokers in 50, the father smoked in the past in 25,, the mother smoked in the past in nine. and in 27 both~ parents smoked in the past. Of the mothers who smoked in the past: 21 smoked during the pregnancy of the twins. Fathers who smoked in the past stoppe&

:8t Cirvuiauon tiol~ 81. No 2 FcDnlan 1990 smoking 10.0c6:7 years before evaluation. though five stopped smoking within 1 year of the studv. Mothers who smo'red in the past stopped smoking 8.6e7.3 vear5 before evaluation with seven stopping within l v_ ear of the study. In~ 105 families. either or both parents were ciga- rctte smokers at the time of evaluation. and maternal smokin¢ during pregnaney occurred in 69 of'these. In the 105 smoking families. the father was the only smoker in 445e. the mother in 32Cic. an6both parents were smokers in 24%. The fathers began smoking at 18.:=6.?2 years of age andipresently smoke 24.5=12.6 cigarettesidav. The mothers began smoking at 3$!4es'.3 years of age and presently smoke 18.5e9.7 cigarettcsidav: The total daily number of cigarettes smoked by the parents ranged from 1 to 10 in 179'e. 11 to 20 in 32~c. and'~was greater than 20 in 51c. Data were obtained and anaKzed on 105 passive smoking twin pairs and 111 nonrpassivc smoking twin pairs. Of the non-passive smoking twin pairs. 611 were monozygotic and 50werc dizygonc. while of the passive smoking twin pairs. 55 were monozygotic and 50 were dizygottc. None of the twins had ever smoked cigarettes. Indexes of passive cigarette smoke exposure were obtained by measuring serum levels of cotinine and thiocyanate. The passive smoking twins (n=35) dem- onstrated higher levels of thiocyanate than the non- passive smoking twi.ns-(n=89) (7,1=43 vs. 3:1="t0 mgrl. p<0.0001): Passive smoking boys and girls had similar elevations of thiocvanate (7:0_4.1-Vand :.3s4.5 mg:1; respectivelv): Cotinine was not detected in non-passive smoking twins but was pres- ent in passive smoking twins (1.5s3.1 ng/tnl),'and serum thiotvanate level correlated witli the cotinihc kvel (r=0:4~4. p<0.005): The level of thioc* vanate in non-passive smoking twins is best explained by non- tobacco: dietarv sources of thiocti•anate as we can exclude the possibility of significant smoke exposure outside their homes due to the absence of cotinine in their blood. The intrarwin pair correlation for thio- cyanate was high (r=0.94„p<0.0001)i demonstrating thatl twins within a smoking family generally have similar exposure to home envtronmentalt cigarette smoke. - Within all smoking families, thiocvanate level cor- related with the total number of cigarettes smoked each dav (r-0.35, p<0.0001). In a subgroup of smok- ing families.in which the mother but not the father smoked (n=14)„ there was good' correlation betwcen thiocVanate level in the twins and the number of cigarettes smoked each day by the mother (r=0S7, p<0.01) (Figure 1), whereas in families in which the father was the only smoker (n=38), no correlation was found. This suggests that paternal cigarette smoking provides little or no contribution to the home passive smoking environment and that mater- nal cigarette smoking is the major source of child- hood passive smoke exposure. The unadjusted data on passive smoking and non- passive smoking groups as a whole and separate& by 10 sa f aJ I 0 6 10 15 20 25 30 35 40 .asa" 0..Rrrrasio. F1GtiRE 1. Plor of the relauon of chdd serum rhiocvanare level to number of csgarrnes smoked each day b+ the mother Plorred points represenr data (rorrt 14 pasrwe smolang chil- dren_ Kendail'7au B corrrlauon coef,Ticunt-0.57: p<0:t11P sex are presented in Table 1. while variables of interest after adjustment for age. height~ weight. and sex are presented in; Table 2: Passive smoking and nonsmoking groups were similar for age. Tanner stage. height. systolic blood pressure. and diastolic bloo& pressure. Girls were more advanced tn~ sexual development by Tanner stage than boys in both non-passive smoking and passive smoking groups (p<0.01); Passive smoking children wcighcd slightlyy more than non-passive smoking children. The hematologic data on passive smoking and non-passive smoking groups are shown in Tables 1 and 2. The mean hernatocnt value was similar for the two groups. Pussive smoking children had' higher whole blood levels of 2.3-DPG. While this difference was significant• ia- the bm a similar trend wass present in~the girls. Insmoking familirs. the 23-DPG level correlated direetlv with the serum thiocvanate ltvei and the total number of cigarettes smoked by the parents (botft: p<0.05),. The relation between the 2.3-DPG level and the serum thiocvanatc level in passive smoking children (r-0129, p<0.02) is shown, in Figure 2. Quantitative lipoprotein chol'estcrol levels arr pre- sented in Tables 1 and' 2. The mean time elapsed from the last; meal to the time of' blood drawing was 6:3 hours and was similar for passive smoking and non-passive smoking groups. ln our, population. the duration of fasting did not contribute to the variance of either total~ cholesterol or, lipoprotein levels.=' 32te passive smoking group had significantly lower total cholesterol than the non-passive smoking group. Passive smoking boys hadslightl~ higher total choles- terol and low densitv lipoprotem (LDL) cholesteroll levels than non-passive smoking boys. though these differences were not statistically significant. How- ever, passive smoking girls had significanti} lower levels of total cholesterol and LDL cholesterol when compared with non-passive smoking girls. Significant intergroup differences were seen in the HL"' cholesterol subfractions. Total HDL choles- tere: was lower in the passive smoking group when compared with the non-passive smoking group: even after adjusting for age. weight. height. and sex. This N C N , ~., ~ l Y ~

.Noskowu-- er al Passive Smoking Effects io Children T.at:r 1. Cnadjusted SteancSD for Passive Smoldng and'VonsmoYdn= Twin Groaps .AJI ewms Bovs G i rts VonsmoYung (n=11'1) Passive smoiung In=105) NonsmoKing tn=56) Passive smoking Ih- 501 Nonsmoking (n- 55) Passive smoK n¢ Aae 11.8= 1.= 11.9e:1.. IJ.Oc1.i 1118=1.1 11.6'c1.0 1L9_ l'.3 Tannen Z6c 1._' ?..=1.3 _.5= 1.= ::4=1i: 18=1.3 3.0_ 1 _ Height(cmi 1s9:1c9.9 150:5=9:1. 150.0=11.4 149.bc9.1 1i8':.=8:_ 151111=9 1 %keight tkgi 398_9.9 s0.1=9.1 s3.:c11.8 39:6=88 s3.0=109 Heart rate 16e3ts mtno "_:9_1_:5 "_:6=1:a 677_9.2 691_10.5 7". 13.3 '6 133 SBP (mm Hg) 106.99.9 109 1=9.6 106.3 = 10.5 11A 1_ 10.6 107 5_ a._ 10fi 5:6 DBP (mm Hg), 59:_c11.5 61.5 =10.8 57.8=11.4' 6i.0ec13.0 61.'=11.a 6:.Oe3:6, Hematocnt (1c-t ) 39,8=1.9 39.5_2.. s0:6x 1.9 s0;0t'_.5 39,6c 11.8 39: 1=1.3 DPG I Aam,-ml1 1.98=0.28 _.08c0.23" 1.89=0.26 ':08ec0!_3t _.05_0::7 =.08e11_- Cholesterol't mg~c 1 17~.8e'4.8 164.3 c 29S • 168:_cZ-'.0 170.1=31.2 1R?,3=26.8 158.6' c_6.d: LDL (mgc'c) 86:5=19.5 gls7_2P8 81.6c 17.8 85.0_23.2 91.4_ 20.1 78._ __0.t)x HDL (mg,%) 49.5c9.3 a5.7=10.st 49.3_8.8 35.2=9,6' s97c9.7 i6:1=11._ HDL- (mgc"c) 1'3.9_'4 121 s 7.1 13.6e7.2 10.8e:6:3' 141.2=7.6 13:==' - HDL.Img~"ct 35'_6.5 33.6 _ 5.8' 35.8c5' a 3<.4_5.8 35.5=7.6 3_:9=5.8' LH 1.80=0:5: 1.88 c0:67 1170c0;47 1'.95_0.6a' I.90=0:55 1.81 c0.69 LVM(g) 90.8_ 18.5 99 1=:1.5• 96.8=19.1 104?='_0.7 85a_16a 93:9_'la DBP. dtastouc 51ood pressure: DPG. =.3-diphosphoglycetate: HDL high denstry ltpoprotetn.cholesterolrLDLn low denstty lipoprotein cholesterol. LH. LDLHDL rano: LVM: left ventncular mass: SBP. systolic blood pressure. •p<t3.A5: rp<0.01; :p<0:001,. comparison is shown in Figure 3. The LDL'HDL ratio was significantlv elevated in~ the passive smoking boys, though the difference lost significance ( p=0.06) after the data were adjusted. The HDL, cholesterol subfraction level was consistendv lower in all the passive smoking groups but this difference reached significance onl±v for the unadjusted levels in the bovs. An inverse trend was found between the total number of cigarettes smoked daily by the moth- ers and the serum HDL cholesterol level in the children. The lowest HDL2 cholesterol level5 were found in boys exposed to the highest number of cigareotes smoked dai.ly by their mothers. These differences however did not meetstatistical signifi- cance. The HDL, subfraction was significantly lower in the passive smoking group than the non-passive smoking group, with greater differences seen in the girls. Because of'the observed influence of maternal but not paternal cigarette smoking on oxygen transport and lipoprotein profiles, we investigate& the possibil- ity thar maternal: smoking may have affected childrenn during gestation. We therefore compared the data adjusted for age, height. weight. and sex, obtained on one twin per family who never ha& exposure to cigarette smoke (n=33) to that of twins exposed onlyy during gestation by maternal' smoking (n=8). An effect of fetal exposure on the HDL cholesterol Ievell was found'with Lower HDL cholesterol, levels in~those children exposed in utero (44:6_2.2 vs. 50.2_ 1.1 mg/dl, p<0,05), though the sample size was quite small; No other significant~ differences were found between these groups. Echocardiograms suitable for measurement were obtained on 74 non-passive smoking and 66 passive smoking twin pairs. Left ventricular internal dimen- Tst.r 2: `LnnsSD in Passi.e Smotin>j and Wonsmok/ns Twin Groups Alt+cr Adjustment for -Age, wekgbt Height and Sex All twtns Boys Giris Noasmokiag (n-111) Passre smoking (n- 105) - 'Vonsmoiung . (n- 56) Passne smolang (n- 50) Nonuaolung (n-55)', Passrve smoiung (n=55) DPG (µmrmi) 1.97c0:03 2:09=0.033 1.90x0.0t 2.08:0.0it 2A3s0.04 ..10c0;04 Cholesterol (mg%) 172?_2:7 164.1c2.7• 168.9c3.7 169.8e3:7 176.6e3.7 157.6=3.71 N LDL(mgO7r) 861_2:0 81.3c2.0 81.8c..8 84.7_2:9 910x2.J 775:.'i HDL(mg°JO), 39:1_0.9 46.0s0A• 49.11=1.3 45.5c1..3 492c1_4 a64_1.s lv IiDL; (mg'7c) 13:5c0.7 12.5c0:7 1'3.2=0:9' 11.3c0.9 13.9=1.0 13:5_ 11.0 HDL3 (mg9c) 35.6-0.6 33.5x0:6' 35.9=0.8 34.1c0.8 35.3c0.9 32.8c0.9. ~ 1.H 1:81s0.05 1.86e:0.06 1.72c0:08' 1.9te:0.08 1.90c0.55 1.81e0.69 ~ LVM (gy 93.6x1.7 95.9t- 1.8 100.9=2:6 100.2c2.8 87.3=2.i 91 lc_.5 DPG. 2.3-diphosphogivicerate: LDL ]owdenstty lipoprotem; HDLL high denstty, IipoprotemxLH. LDLliDL rano: LVTwt. left ventrtcutar <0 05: tp<0 001 mass ' 01: ; <0 ~ .. . p . . p .

Circulation Vol 81; , :y'o 2: Febnran 1990' . 2 u1 ".4 tA 0 21 #4I d t2 t4 L• t/ 2.0 2.2 2.4 2s a,to.+m.+oa.ca+sta krZal FiGtRE 2. Plot of the relanon between whole blood 23- diphosphoglvicerate lemt' and the serum thtocyanare level in -passive smoking childrrn /n=351' 1Cenda!!'Tay B correlanon coeffictent=0.29, p<0.02: sions in svstolt an& diastole were the same for the two!groups. The passive smoking group was found too have a higher left ventricular mass than.the nonsmok- ing group, though the difference was lost after the data were adjusted for bodv size (Tables 1 and 2)t Covariates of smoking behavior and~ other con- founding variables were considered, which~ could have affected the results. When parental income. educatiom level, years of education, and beer and liquor consumption were compared between parents in smoking and nonsmoking families, no differences were found. When we compared the exercise level (the number of times each week vigorous exercise was perfotmed)i in the twins themselves, the number of exercise episodes each week were similar for passive smoking and~ non-passive smoking boys (4.7_2.0 vs. 4.2_2.3, timestwk) and' for passive smoking and non-passive srnoking girls (4.3_2.3 vs. 4.7_2.1 timesiwk). X= tests showed no association between smoking status and~ exercise in either the boys (X==1.7; p<0.2) or the girls (X==0i5, p<0.5). A preliminary estimate of the heritability of spe- cific variables was obtained! using the study's twin~ 51 72 0 E _J s0a 49 ~ 49 ~ c 47 ~ _ 46 J 45 ~ 0 ti non-smoklhp t7 paasiw smoking F1oUttE 3. Bar graph of the comparuon of total senun HDL cholesterol'level ih,non.-passive smolang (n=106)~and passtve ~ stnolang (nr=102) childnn after adjusting for age. sex height. and wetght: Data reprrsentgroup mean_SD. 'p<0.05. HDL, htgh densuv lipoprotetn. TABtE 3. l:ntrap.ir Twin Correlations and Heritabilit. Monor,vgouc In- 1161 Dtzvgouc /R=1007 Hcntabdin. w'i SBP 0:91 0:66, 01S 033 68C? 66°'r SC'r 0.94 0j91 bc'r DPG 0:65 0~31 38C"c LDL 0.81 0:35 92Ci HDL 0.81' 04: 78I-r HDL- 0.81 0.36 g8C-r HDL,, 0.53 0:50 6C-r All monozvgouc twm cortelauons are stgmficant at p<O.OOtl11. All dtzygouc Twtn correlations are signtficant at p<Oi005. NYr. wetght: SBP, systo{ic blood pressure: SCN. thiocvanate. DPG. 23-diphosphoglycerate: LDLL low densttv hpoprotmn: HDL high density lipoprotem: design. Intrapair twin correlations for identical and nonidentical'twins are shown in Table 3. The herita- bilitv is indicative of the variation attributable to genetic effects. The correlation for identical twins is significantlv higher than for nonidentical twins for all variables except serum thiocyanate an6 HDL, cho- lesterol levels- Within sampling error. the monozygotic correlation is twice the dizygotic correlation for svstolic blood pressure. HDL cholesterol. HDLA cholesterol, LDL cholesterol, weight, and left ventricular mass. These values are expected if mating is random,with respect to the causes of juvenile measures, gene action is additive, and familw environment does not cause twin resemblance.These data also indicate that a high proportion of the variation in thiocyanate and HDL, cholesterol levels is attributable not to genetic effects but to environmental effects, such as passive srnoking: The variation in 2.3-DPG levels appears balanced between genetic and environmental effects. Discussion We found alterations in systemic oxygen transport and lipoprotein composition in preadolescent chil- dren that were related to cigarette smoke exposure. Paternal smoking did not influence measures of passive smoke exposure. while maternal smoking affected children by providing passive smoke expo- sure in the home an6possibiv during gestation. Our results indicate that, as in other tissue hypoxia states (anemias, chronic pulmonary disease, cyanotic heart disease, and~ high altitude), the body attempts to compensate for hypoxia by increasing the 2.3-DPG level in the blood to meet tissue oxygen require- menu.. A hypoxia-driven mechanism to trigger 2-3- DPG synthesis may be responsible for the increase in 2.3-DPG level in active smokers.'"" Ervthrocytosis occurs frequently in ad'ult active smokers. Hematocrit elevation: in active smokers has been ascribed to long-term exposure of even~ low levels of~ carbon monoxide, which results in tissue hypoxia and leads to increased red cell mass.=• Hematocrit values for the passive smoking and; non-

passive smoking children in the present study were id'entlcal. though both groups were m the early stages of pubertal' development. Steroid and adenohv= pophyslal hormones. which positively influence en•thropotesis.:5are low in preadolescent children and progressivelv increase during puberty. Longitu- dinal evaluation of passive smoking an6 non-passive smoking twins as they progress through puberty may detect differences in hernatocrit and other oxygen transport vanabfes. which may be related to the d'e¢ree of passive cigarette smoke exposure. The incidence of atherosclerotic coronary arterv disease is stron¢1'v associated with increased levels of -- LDL cholesterol~ and decreased levels of HDL cho- lesterol. especially the HDL, cholesterol subfrac- tion.=6-= Active cigarene smoking alters the total serum cholesterol concentration and' lipoprotein composuion, which directlv increase the risk of cor- onary heart disease. In our population. children with a family history of premature cardiovascular death had lower levels of HDL,, cholesterol than those without such a historv.=,' During puberty and early adolescence, levels of HDL and LDL cholesterol decrease in all children. but the decrease in HDL cholesterol is more pro- nounced in boys than in g>,ris.=s Since the girls in our study population were more sexually developed than the boys. we cannot exclude the possibiliry that the passive smoking girls were more advanced in~ puber- tal development than their non-passive smoking counterparts. whi& could explain the observed dif- ferences in LDL cholesterol. MDL cholesterol levels fall during puberrv in boys in~ association with increases in testosterone levels.29 Passive cigarette smoking, by further diminishing the level of HDt,i cholesterol in pubertal I males. may be associated with accelerated'atheroscierotic changes and an increase& risk of coronary heart disease.. The passive smoking preadolescent boys demon- strated, a tendcncy toward lower levels of the HDL: cholesterol subfraction, which was related to the number of cigarettes smoked daily by the parents of the boys. Because Bodurtha et a12f showed that coronary heart disease deaths occur more frequently in families with low levels of HDL, cholesteroi, a lower HDL.G cholesterol level inipassive smoking boys likely represents an enhanced atherogenic risk factor for the subsequent develbptnent of athcrosclerotic coronarv heart disease. Haffncr et al30 found a reduction in HDL, choles- terol subfraaion levels with active cigarette smoking. These authors also found that alcohol consumption raised HDL,, cholesterol Ievels. It appears therefore that HDL,3 , cholesterol levels represent a reactive lipoprotein species that responds to specific environ- mcntal influences. Our data support this hypothesis by not only demonstrating Ibwer HDL, cholesterol levels in passive smoking children but also the low heritabil- ity of HDL,, implying high environmental variance. .Nosliowtc er al Passive Smoking Effects in Children : o,i Acknowiedgments We acknowledge the technlcal expertlse of A. Cook L. Stevenson. B. Toms, K. Vincent. C. Dick- cns. W. Wilson. M. Blanchard- and P. Winter. References l, US Department of Health and: Human Services: Fhe Nealin Conseouences of S.noweg: Cancer. ,.4 Reporr o,l the Surpron GeneraL' DHHS publication No. (PHS) 82•50179 Roucvsllt:. Md. 1982 :. US Departmenr of Health and Human Services: The Heal:h. Contequenca Of Snwkutq: Cardiovascuiar Dcsease. .a Report or the Sur;eon GenaaL DHHS pubiicatton Yo. IPHSI 8s-50_0s Rock.ille. Md. 1983 3. US Department of Health and Human,Servmces: The Ffeauh Con:equeneerof SrnokmS: C/wnec Obseucnve Lun; Deuase. .a Report o/the Sur;eon Genera[ DHHS publicacton No. fiPH51 8a- 50205. Rocirvtue. 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