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Elevated Blood Pressure with Reduced Left Ventricular and Aortic Dimensions in Adolescents Born Extremely Preterm
Elevated Blood Pressure with Reduced Left Ventricular and Aortic Dimensions in Adolescents Born Extremely Preterm Remi R. Kowalski, MBBS1,2,3, Richard Beare, PhD4, Lex W. Doyle, MD3,5,6, Joseph J. Smolich, PhD1,3, and Michael M. H. Cheung, MD1,2,3, on behalf of the Victorian Infant Collaborative Study Group* Objective To evaluate the long-term cardiovascular effects of extremely preterm birth in a cohort of adolescents followed prospectively, who were largely free from intrauterine growth restriction. Study design Central blood pressures, aortic and cardiac dimensions, left ventricle (LV) function, pulse wave velocity, augmentation index, and microvascular reactive hyperemia were measured in 18-year-old subjects born extremely preterm at <28 weeks’ gestation (n = 109) and term-born controls (n = 81). Results Compared with controls, preterm adolescents had higher systolic (124 13 vs 118 10 mm Hg, P = .002) and diastolic (72 8 vs 67 7 mm Hg, P < .001) blood pressures, but lower ascending aortic z-scores (0.13 0.89 vs 0.42 0.78, P = .02), LV diastolic (48.5 4 vs 50.3 4.5 mm, P = .007) and systolic (30.2 3.5 vs 31.9 4.0 mm, P = .003) diameters, and a reduced LV mass (130 34 vs 145 41 g, P = .01) and mass index (75 14 vs 81 16 g/m2, P = .02). However, LV relative wall thickness, LV function, pulse wave velocity, augmentation index, and microvascular reactive hyperemia were similar. Within the ex-preterm group, there were no significant relationships between birthweight z-scores and any cardiovascular measures, once the latter were adjusted for current body size. Conclusions Extremely preterm birth had relatively minor cardiovascular effects in late-adolescence, with increased blood pressures, decreased LV, and aortic size, but preserved LV function, macrovascular properties, and microvascular function. In utero growth was not independently related to cardiovascular function within the ex-preterm cohort. (J Pediatr 2016;-:---).
L
ow birthweight and prematurity predispose to higher cardiovascular morbidity and mortality in adulthood.1-4 Indeed, vascular abnormalities may be evident by adolescence or early adult life, including an elevated pulse wave velocity (PWV),5,6 increased carotid intima-media thickness (cIMT),6,7 aortic narrowing,5,8,9 and impaired microvascular func7,9,10 tion. More recently, increased left ventricle (LV) mass with increased LV wall thickness and reduced luminal diameter has been reported in ex-preterm young adults.11 Ex-preterm subjects are heterogeneous, however, as they may have in utero growth restriction (IUGR), be small for gestational age (SGA) or appropriate weight for gestational age (AGA) at birth, and also because prematurity can span moderately preterm (32-36 weeks’ gestation), very preterm (28-31 weeks’ gestation), and extremely preterm (<28 weeks’ gestation) categories. The latter category is increasingly relevant as survival of babies born extremely preterm has improved dramatically over recent years.12 Thus, studies in ex-preterm adolescents and adults born at varying gestations and with varying in utero growth impairment have suggested that increasing prematurity is associated with greater vascular dysfunction6,7 and LV mass.11 By contrast, evidence from small cohorts of extremely preterm but AGA infants and children suggests that, even though From the Heart Research, Murdoch Children’s blood pressures may be elevated,13 no differences exist between AGA exResearch Institute; Department of Cardiology, Royal 13 14 Children’s Hospital; Department of Pediatrics, preterm and control groups in LV mass index, PWV, or microvascular dilaUniversity of Melbourne; Developmental Imaging, tion.15 However, whether additional cardiovascular abnormalities emerge as Murdoch Children’s Research Institute; Research Office, Royal Women’s Hospital; and Department of extremely preterm subjects progress toward adulthood is unknown. Obstetrics and Gynecology, University of Melbourne, Parkville, Victoria, Australia The main aim of the study was to define longer-term cardiovascular sequelae *Additional members of the Victorian Infant Brain Study of being born extremely preterm, comparing results with term-born controls, Group is available at www.jpeds.com (Appendix). who have been followed since birth as part of the Victorian Infant Collaborative Supported by the National Health and Medical Research 1
2
3
4
5
6
AGA AIx BSA cIMT IUGR LV PWV SGA
Appropriate weight for gestational age Augmentation index Body surface area Carotid intima-media thickness In utero growth restriction Left ventricle Pulse wave velocity Small for gestational age
Council, Canberra, Australia (491246 to [to L.D., P. Anderson, S. Wood, C. Robertson, S. Hope, D. Hacking, J. Cheong]); Center for Clinical Research (Excellence Award 546519 [to L.D., P. Davis, T. Inder, P. Anderson, C. Kuschel, R. Hunt, J. Cheong, D. Hacking); Center of Research Excellence (1060733 to [L.D., P. Davis, P. Anderson, R. Hunt, J. Cheong, S. Jacobs, G. Roberts, A. Spittle, D. Thompson, J. Dawson]); the Victorian Government’s Operational Infrastructure Support Program (Post-graduate Scholarship to R.K.); and the Royal Children’s Hospital Foundation, Melbourne, Australia (Big W and RCH 1000). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.020
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Study.16 In addition, we aimed to assess the effect of IUGR on the cardiovascular measures within the extremely preterm cohort alone.
Methods After study approval from the institutional Human Research Ethics Committee and written informed consent, participants were recruited from the Victorian Infant Collaborative Study cohort, which included all extremely preterm (gestation <28 weeks) or low birthweight (<1000 g) survivors born in Victoria, Australia in 1991-1992.16 The original cohort was comprised of 298 preterm survivors and 262 control infants. Control infants were born in maternity hospitals housing neonatal intensive care units, had birthweights of >2499 g, were randomly selected from births on the due date of the preterm survivor, and were matched for sex. Of the original cohort, only a subset of 109 subjects born <28 weeks’ gestation and 81 control subjects were able to attend the Royal Children’s Hospital for anthropometric and blood pressure measurements, echocardiography, and vascular assessment at 18.0 0.9 (mean SD) years of age. Anthropometric and blood pressure data at 18 years from both cohorts have been reported elsewhere.17 All the measurements were performed in a single session by the same technologist who was unaware of subjects’ group classification. Presence of renal disease, diabetes mellitus, smoking status, and family history of hypertension were recorded after taking a clinical history. Subjects were asked to abstain from alcohol, tobacco, and caffeine for $24 hours, and were fasted for $6 hours prior to study. Body surface area (BSA) was calculated by the formula of Dubois and Dubois,18 with body mass index defined as weight (kg)/height (m)2. After 10 minutes of semirecumbent rest in a quiet darkened room, right brachial blood pressure was recorded in triplicate using a blood pressure cuff width that was greater than 40% of the upper arm circumference, with a digital oscillometric monitor (HEM 705-CP; Omron, Kyoto, Japan).19 Ambulatory blood pressure was measured for 24 hours using the Oscar 2 ambulatory blood pressure monitor (SunTech Medical Inc, Morrisville, North Carolina). Measurements were performed one-half hourly when awake, and hourly when asleep, and generated systolic, diastolic, and mean blood pressure values at each time point. Echocardiography (Vivid 7; GE Medical Systems, Horten, Norway) was performed in semirecumbent patients according to American Society of Echocardiography guidelines,20,21 using a 5 MHz transducer for cardiac and aortic sonography, and a 10 MHz linear probe for carotid imaging. Ascending aortic, left atrial, and LV diameters were obtained using Mmode and normalized by z-scores.22 To assess LV systolic function, fractional shortening was calculated from M-mode and ejection fraction with Simpson biplane method, and diastolic function was evaluated with transmitral Doppler velocities, isovolumic relaxation time, and tissue Doppler analysis. 2
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LV mass was indexed to BSA.23 Relative wall thickness was calculated as (LV posterior wall + interventricular septal dimensions)/LV end-diastolic dimension. Right common carotid and radial artery pressure waveforms were obtained with an applanation tonometer (SPT301 Transducer, Millar Instruments, Houston, Texas) interfaced to a SphygmoCor system (AtCor Medical, Sydney, Australia). The central aortic pressure profile was obtained by mathematical transformation of the radial signal and augmentation index (AIx) then derived after determination of the ascending limb inflection point.24 The carotid pulse-to-sternal notch and sternal notch-toright radial artery distances were measured to the nearest cm, with carotid-radial PWV calculated as carotid-to-right radial artery path-length divided by the difference between arrival time of the pressure wave foot at these two sites.25 The cIMT was measured offline in the right common carotid artery posterior arterial wall, 1 cm proximal to the carotid bulb,21 using wall-tracking software (EchoPAC, GE Vingmed Ultrasound, Norway). Microcirculatory responses were assessed using the EndoPAT system (Itamar Medical, Caesarea, Israel), with probes placed on the tips of both index fingers. After a period of equilibration, a left arm blood pressure cuff was inflated to 50 mm Hg above systolic pressure for 5 minutes, with reactive hyperaemia recorded after cuff deflation.26 Statistical Analyses Data were analyzed with SPSS (v 20; IBM Corp, Armonk, New York), with normality assessed using Levene’s test. Between-group data were compared with an independent Student t test for continuous normally distributed data and c2 analysis for categorical variables, with results presented as mean differences (95% CI). To detect if differences between groups were sex-specific, we ran regression models including an interaction term for sex and group; if the interaction term was significant, group differences were compared within each sex separately. To assess the associations of the cardiovascular measures with IUGR within the ex-preterm cohort, we regressed the various measures against the birthweight SD score, calculated relative to the British Growth Reference.27 With 109 preterm subjects and 81 controls, the study had 80% power to detect a mean difference between groups as small as 0.41 SD. Within the ex-preterm cohort alone, the study had 80% power to detect a correlation coefficient between continuous variables as small as 0.26.
Results As expected, although predominantly AGA, ex-preterm subjects were smaller at birth, with a trend toward lower birthweight z-scores (Table I). Only 2% of our pre-term study cohort were born SGA (birthweight z-score < 2 SD), with no SGA patients in the control group. At the time of the cardiovascular study, corrected age, weight, and body mass Kowalski et al
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Table I. Subject demographics and blood pressure variables At birth Gestational age, wk Birthweight, g Birthweight z-score Male SGA (z-score < 2 SD) Antenatal corticosteroids At study Corrected age, y Height, cm Weight, kg BSA, m2 BMI, kg/m2 Smoking at 18 y of age Family history HT HR, beats per min Brachial SBP, mm Hg Brachial DBP, mm Hg Brachial MBP, mm Hg Brachial PP, mm Hg Ambulatory blood pressure SBP 24 h, mm Hg DBP 24 h, mm Hg MBP 24 h, mm Hg
Ex-preterm (n = 109)
Control (n = 81)
P value
Mean difference (95% CI)
25.7 1 896 169 0.2 0.86 59 (54.1%) 2 (1.8%) 78 (71.6%)
39.1 1 3398 437 0.04 0.9 33 (40.7%) 0 (0.0%) 1 (1.2%)
<.001 <.001 .07 .08* .51* <.001*
13.4 (13.0, 13.7) 2502 (2400, 2604) 0.24 ( 0.02, 0.49)
17.9 0.8 166.7 9.8 64.5 14.9 1.7 0.2 23.3 5.1 27 (24.8%) 54/78 63 13 124 13 72 8 89 8 52 12 n = 91 131 13 71 8 91 9
18.1 0.9 170.3 8.1 66.9 13.7 1.8 0.2 23.0 3.9 18 (22.2%) 35/60 60 10 118 10 67 7 84 7 51 9 n = 71 127 13 68 8 88 9
.13 .007 .24 .05 .72 .73* .21* .14 .002 <.001 <.001 .67
0.2 ( 0.1, 0.4) 3.6 (1.0, 6.1) 2.1 ( 1.7, 6.5) 0.1 (0.0, 0.1) 0.2 ( 0.5, 1.1)
.15 .008 .02
3( 5( 5( 5( 1(
6, 1) 9, 2) 7, 3) 7, 3) 4, 2)
3 ( 7, 1) 3 ( 6, 1) 3 ( 6, 1)
BMI, body mass index; DBP, diastolic blood pressure; HT, hypertension; HR, heart rate; MBP, mean blood pressure; PP, pulse pressure; SBP, systolic blood pressure. Values are mean SD or n (%). *c2 test.
index were not different between groups, but ex-preterm subjects were shorter, and had a smaller BSA. No study subjects had structural heart disease, nor history of renal disease or diabetes, and there were no differences in smoking status or family history of hypertension. Ex-preterm subjects had higher brachial systolic, diastolic, and mean blood pressures, but there was no difference in pulse pressure. Ambulatory blood pressure results were available for 91 ex-preterms and 71 controls. Ex-preterm subjects had higher diastolic and mean blood pressures, but the systolic pressure was not significantly different. Compared with those from the inception study cohort who did not participate in this study, there was a higher rate of smoking at 18 years of age in both ex-preterm and control groups, and a lower percentage of males in participating controls, but otherwise there were no significant perinatal or demographic differences (Table II; available at www. jpeds.com). Although left atrial z-scores were similar, LV end-diastolic, LV end-systolic and ascending aortic z-scores, as well as indexed LV end-diastolic and end-systolic volumes, were smaller in ex-preterm subjects (Table III). LV posterior wall thickness and relative wall thickness were not different between groups, but in ex-preterm subjects, the interventricular septal thickness but not z-score was smaller, and absolute and indexed LV mass were lower. Compared with controls, stroke volume was lower in expreterm subjects, but LV fractional shortening, LV ejection fraction, and LV diastolic indices were preserved, with the exception of the LV E’ (early diastolic wave peak on tissue Doppler analysis) velocity, which was lower in the ex-
preterm group. The tricuspid regurgitant velocity and right ventricular isovolumic acceleration were greater in the expreterm group. Neither PWV, AIx, cIMT, nor reactive hyperaemia index differed between groups (Table IV). The only interaction terms for sex that were significant were for measures of ventricular wall thickness (interventricular septal dimension and its z-score, left ventricular posterior wall dimension and its z-score, and relative wall thickness). The differences between preterm and term subjects for these variables were largely found in males, and not females (Table V; available at www.jpeds.com). When adjusted for current size, there were no significant relationships between any cardiovascular measure and birthweight SD score, other than the peak systolic waves in the LV, septum, and right ventricle as assessed by tissue Doppler analysis, which displayed a weak positive relationship with birthweight z-score, even though no such relationship was evident with other measures of systolic function (Table VI).
Discussion A reduced ascending aortic diameter in ex-preterm adolescents was expected, as a decreased abdominal aortic diameter has been reported in AGA or SGA ex-preterm adolescent girls.5 Moreover, the smaller diameter of other major arteries, such as the brachial artery in adolescents10 and the common carotid artery in infants,28 suggests that a generalized growth impairment of systemic arterial vasculature accompanies preterm delivery. Despite finding smaller aortic diameters in our ex-preterm cohort, central AIx was similar between groups, a disparity
Elevated Blood Pressure with Reduced Left Ventricular and Aortic Dimensions in Adolescents Born Extremely Preterm
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Table III. Doppler echocardiographic data Ex-preterm (n = 109)
Control (n = 81)
P value
1.17 1.13 0.42 0.78 8.14 1.21 0.06 0.71 50.3 4.47 0.36 0.86 31.9 3.98 0.38 0.85 7.97 1.17 0.30 0.67 0.32 0.04 145 41 81 16 37 4 66 4 67 12 23 5 78 21 2.28 0.62 66 9 2.0 0.23 10.7 1.62 17.6 2.43 8.4 0.83 14.7 1.92 13.5 2.11 16.0 2.85 3.23 1.3 1.28 0.56 5.88 1.64 1.97 0.71
.95 .02 .02 .18 .007 .02 .003 .005 .57 .46 .93 .01 .02 .05 .09 <.001 <.001 .005 .38 .10 .003 .20 .04 .68 .24 .65 .29 1.0 .29 .10 .002
1.16 1.08 0.13 0.89 7.70 1.29 0.07 0.68 48.5 4.03 0.07 0.77 30.2 3.53 0.03 0.85 7.87 1.16 0.37 0.76 0.32 0.05 130 34 75 14 38 4 67 5 61 10 20 5 70 17 2.2 0.61 68 11 2.1 0.22 10.4 2.11 16.8 2.65 8.3 1.05 14.4 1.74 13.3 2.05 16.4 2.56 3.23 1.56 1.38 0.72 6.32 1.94 2.4 1.05
LA z-score AscAo z-score IVSd, mm IVSd z-score LV EDd, mm LV EDd z-score LV ESd, mm LV ESd z-score LV PWd, mm LV PWd z-score LV RWT LV mass, g LV mass index, g/m2 FS, % LVEF, % LV EDV/BSA (mL/m2) LV ESV/BSA (mL/m2) Stroke volume, mL MV E:A IVRT, ms TR velocity LV S’ wave LV E’ wave Septal S’ wave Septal E’ wave RV S’ wave RV E’ wave LV IVV LV IVA RV IVV RV IVA
Mean difference (95% CI) 0.01 ( 0.31, 0.33) 0.29 (0.05, 0.52) 0.44 (0.08, 0.80) 0.14 ( 0.06, 0.34) 1.73 (0.49, 2.98) 0.29 (0.05, 0.53) 1.69 (0.59, 2.79) 0.36 (0.11, 0.60) 0.17 ( 0.24, 0.43) 0.1 ( 0.28, 0.13) 0.01 ( 0.01, 0.01) 15 (4, 26) 6 (1, 10) 1 ( 2, 0) 1 ( 2, 0) 6 (3, 9) 3 (1, 4) 8 (2, 14) 0.08 ( 0.10, 0.26) 2 ( 5, 0) 0.1 ( 0.17, 0.03) 0.35 ( 0.19, 0.88) 0.78 (0.05, 1.51) 0.57 ( 0.21, 0.33) 0.32 ( 0.21, 0.86) 0.14 ( 0.47, 0.74) 0.43 ( 1.22, 0.37) 0 ( 0.43, 0.43) 0.10 ( 0.30, 0.09) 0.45 ( 0.98, 0.09) 0.43 ( 0.69, 0.16)
AscAo, ascending aorta; E’, early diastolic wave peak on tissue Doppler analysis; EDd, end-diastolic diameter; EDV, end-diastolic volume; ESd, end-systolic diameter; ESV, end-systolic volume; FS, fractional shortening; IVA, isovolumic acceleration; IVRT, isovolumic relaxation time; IVSd, interventricular septal dimension; IVV, isovolumic velocity; LA, left atrium; LVEF, LV ejection fraction; MV, mitral valve; PWd, posterior wall dimension; RV, right ventricle; RWT, relative wall thickness; S’, systolic wave peak on tissue Doppler analysis; TR, tricuspid regurgitation. Values are mean SD.
presumably related to AIx being a composite variable influenced both by arterial stiffness, which was not demonstrably different between groups in our cohort, and global wave reflection.24 The lack of a difference in AIx in our study population is similar to children born very preterm and AGA,29 but differs from the raised AIx reported in a mixed cohort of extremely preterm children, which had a higher proportion of SGA subjects.30 This is in accord with the observation that, in children born very preterm, AIx is higher in SGA than AGA,29 as well as the conclusion that preterm birth and IUGR produce different alterations in vascular growth patterns.31 Extremely preterm birth in our study was not associated with changes in vascular function. Thus, PWV values were similar to published population data,32 and accorded with
Table IV. Vascular function data
PWV, m/s AIx, % cIMT, mm RHI
Ex-preterm (n = 109)
Control (n = 81)
P value
5.6 1.0 9.8 17.9 0.43 0.05 2.01 0.57
5.7 0.9 8.7 16.8 0.43 0.03 2.10 0.56
.28 .67 .93 .32
RHI, reactive hyperemia index. Values are mean SD.
4
Mean difference (95% CI) 0.15 ( 1.1 ( 0.00 ( 0.09 (
0.12, 0.43) 6.2, 4.0) 0.01, 0.01) 0.09, 2.60)
the near-identical PWV observed in AGA children born very preterm or term.14 Large vessel structure assessed by cIMT was also no different, with values similar to those reported for normal adolescents.32 Furthermore, the normal endothelial function in ex-preterm adolescents agreed with the conclusions that brachial flow-mediated vasodilation was not different in young adolescents born AGA, and either very preterm or term,10 and that IUGR, rather than preterm birth, predisposes to endothelial dysfunction.10,31 Our blood pressure findings are similar to reports that both systolic and diastolic blood pressures are elevated in ex-preterm adolescents5,33 and young adults,6,11 and as we reported in our study of ambulatory blood pressure in the whole cohort of preterm subjects compared with controls at 18 years of age, where the changes in blood pressure between study groups were similar to the resting differences presented in this study, with the exception of the ambulatory systolic pressure, which likely reflects the smaller sample size.17 Nonetheless, longer term follow-up is warranted to establish whether this observed slight but significant blood pressure elevation in ex-preterm adolescents predisposes to development of hypertension in adulthood. In a recent study of young adults born prematurely, diastolic and systolic LV diameters were smaller, but LV wall thickness, relative wall thickness, and LV mass index were all higher than controls, with these findings interpreted as Kowalski et al
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Table VI. Linear relationships of blood pressure, echocardiographic, and vascular data with birthweight z-score in ex-preterm adolescents (n = 109) Regression coefficient* (95% CI) Brachial SBP, mm Hg Brachial DBP, mm Hg Brachial MBP, mm Hg Brachial PP, mm Hg AscAo z-score LV EDd, mm LV EDd z-score LV ESd, mm LV ESd, z-score LV IVSd, mm LV IVSd z-score LV PWd, mm LV PWd z-score LV mass, g LV mass index, g/m2 FS, % LVEF, % MV E:A IVRT, ms TR velocity LV S’ wave LV E’ wave Septal S’ wave Septal E’ wave RV S’ wave RV E’ wave LV IVV LV IVA RV IVV RV IVA PWV, m/s AIx, % cIMT, mm RHI
0.40 ( 2.51, 3.08) 0.72 ( 2.58, 1.14) 0.34 ( 2.19, 1.51) 1.12 ( 1.63, 3.87) 0.01 ( 1.91, 2.10) 0.72 ( 0.17, 1.61) 0.03 ( 0.14, 0.21) 0.45 ( 0.34, 1.24) 0.01 ( 0.08, 0.20) 0.25 ( 0.04, 0.53) 0.07 ( 0.09, 0.22) 0.26 (0.00, 0.51) 0.05 ( 0.12, 0.22) 8.88 (1.39, 16.36) 2.65 ( 0.54, 5.84) 0.08 ( 1.02, 0.85) 0.57 ( 0.52, 1.65) 0.10 ( 0.23, 0.04) 1.27 ( 1.23, 3.76) 0.03 ( 0.25, 0.08) 0.60 (0.14, 1.06) 0.05 ( 0.54, 0.64) 0.23 (0.00, 0.46) 0.05 ( 0.34, 0.44) 0.43 ( 0.02, 0.88) 0.13 ( 0.44, 0.70) 0.06 ( 0.30, 0.42) 0.11 ( 0.06, 0.28) 0.01 ( 0.46, 0.45) 0.07 ( 0.31, 0.18) 0.03 ( 0.20, 0.25) 0.30 ( 3.75, 4.34) 0.00 ( 0.01, 0.02) 0.03 ( 0.11, 0.16)
% variance explained
P value
0.1 0.6 0.1 0.6 0 2.4 0.1 1.2 0 2.7 0.7 3.5 0.4 4.9 2.5 0 1 1.8 1 1.1 5.9 0 3.6 0.1 3.3 0.2 0.1 1.7 0 0.3 0.1 0 0.01 0.1
.79 .44 .71 .42 .94 .11 .71 .26 .94 .09 .38 .05 .53 .02 .1 .86 .31 .17 .32 .31 .01 .87 .05 .81 .06 .66 .74 .20 .97 .58 .82 .88 .45 .71
*Change in cardiovascular variable per unit change in birthweight z-score.
evidence of accelerated cardiomyocyte hypertrophy during postnatal growth.11 By contrast, although LV cavity diameters were also smaller in our ex-preterm adolescents, LV wall thickness and mass were generally lower than in controls (Table III), implying an attenuation of postnatal LV growth. One possible basis for this difference relates to an effect of IUGR, as ex-preterm subjects in the study of Lewandowski et al11 were part of a mixed cohort, with 30% SGA and only 14% born extremely preterm. Indeed, IUGR appears to stimulate cardiac growth, as it resulted in an increase in LV mass index in term neonates,34 and LV wall thickness and mass were increased in late gestation fetal sheep following growth restriction produced by placental embolization.35 Thus, postnatal LV growth patterns after preterm birth may also be heterogeneous, and influenced by coexistent IUGR.31 A possible contribution of methodological differences also needs to be considered, as we used M-mode echocardiography to obtain LV mass, whereas Lewandowski et al11 used magnetic resonance imaging. Magnetic resonance imaging estimates of LV mass are more accurate as these do not involve assumptions about LV chamber geometry.36 Nonetheless, the use of different imaging modalities does not
explain the disparate findings of LV wall dimensions and relative wall thickness between our study (Table III) and that of Lewandowski et al.11 As in a mixed cohort of ex-preterm young adults,11 LV stroke volume was lower, but LV ejection fraction similar to control subjects; as in ex-preterm AGA children,13 LV transmitral velocity ratios were not different from control subjects, with only a minor reduction in LV E’ (early diastolic wave peak) tissue Doppler velocities, but no other tissue Doppler abnormalities to support significant reduction in diastolic function. Taken together, our findings suggest that LV systolic and diastolic function were preserved in expreterm and AGA adolescents, although we cannot exclude the possibility of differences in myocardial deformation patterns.11 Our study had several limitations. To allow equilibration of the physiological state and correlation of vascular and echocardiographic variables, the blood pressure was measured in a semirecumbent position, for which there are no normal blood pressure data published. The observed blood pressure differences between the 2 groups remain valid, however. We did not measure blood glucose or lipids, so any potential confounding effects of group differences between serum glucose and cholesterol levels on study results could not be assessed. Although there was insufficient power to classify the ex-preterm group by SGA/AGA status, there was no evidence of substantial relationships between growth restriction in utero and any of the cardiovascular variables, once adjusted for body size at adolescence. Finally, as no previous LV and vascular structural and functional assessments had been performed in our study groups, the effects of childhood growth and puberty on measured variables could not be specifically evaluated. Our findings suggest that, in the absence of coexistent growth impairment, adolescents born extremely preterm do not exhibit major cardiovascular abnormalities as they enter adult life. Continued follow-up is required to fully characterize the long-term cardiovascular sequelae of this cohort. n We thank Jane Koleff for acquisition of echocardiographic and vascular function data. Submitted for publication Oct 8, 2015; last revision received Dec 15, 2015; accepted Jan 6, 2016. Reprint requests: Remi R. Kowalski, MBBS, Department of Cardiology, The Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia. E-mail: [email protected]
References 1. Gennser G, Rymark P, Isberg PE. Low birthweight and risk of high blood pressure in adulthood. BMJ 1988;296:1498-500. 2. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens 2000;18:815-31. 3. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989;298:564-7.
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4. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938-41. 5. Bonamy AK, Bendito A, Martin H, Andolf E, Sedin G, Norman M. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls. Pediatr Res 2005;58:845-9. 6. Lazdam M, la Horra de A, Pitcher A, Mannie Z, Diesch J, Trevitt C, et al. Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism? Hypertension 2010;56:159-65. 7. Hovi P, Turanlahti M, Strang-Karlsson S, Wehkalampi K, Jarvenpaa AL, Eriksson JG, et al. Intima-media thickness and flow-mediated dilatation in the Helsinki study of very low birthweight adults. Pediatrics 2011;127: e304-11. 8. Bjarnegard N, Morsing E, Cinthio M, Lanne T, Brodszki J. Cardiovascular function in adulthood following intrauterine growth restriction with abnormal fetal blood flow. Ultrasound Obstet Gynecol 2013;41:177-84. 9. Brodszki J. Impaired vascular growth in late adolescence after intrauterine growth restriction. Circulation 2005;111:2623-8. 10. Singhal A, Kattenhorn M, Cole TJ, Deanfield J, Lucas A. Preterm birth, vascular function, and risk factors for atherosclerosis. Lancet 2001;358: 1159-60. 11. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, Francis J, et al. Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function. Circulation 2013;127:197-206. 12. Field D, Draper ES, Fenton A, Papiernik E, Zeitlin J, Blondel B, et al. Rates of very preterm birth in Europe and neonatal mortality rates. Arch Dis Child Fetal Neonatal Ed 2009;94:F253-6. 13. Morsing E, Liuba P, Fellman V, Marsal K, Brodszki J. Cardiovascular function in children born very preterm after intrauterine growth restriction with severely abnormal umbilical artery blood flow. Eur J Prev Cardiol 2014;21:1257-66. 14. Cheung YF. Relation of arterial stiffness with gestational age and birthweight. Arch Dis Child 2004;89:217-21. 15. Bonamy AKE, Martin H, J€ orneskog G, Norman M. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med 2007;262:635-42. 16. Doyle L. Outcome at 2 years of children 23-27 weeks’ gestation born in Victoria in 1991-92. The Victorian Infant Collaborative Study Group. J Paediatr Child Health 1997;33:161-5. 17. Roberts G, Lee KJ, Cheong JLY, Doyle LW. Higher ambulatory blood pressure at 18 years in adolescents born less than 28 weeks’ gestation in the 1990s compared with term controls. J Hypertens 2014;32:620-6. 18. Bois Du D, Bois Du EF. Clinical calorimetry: tenth paper a formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863. 19. O’Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001;322:531-6. 20. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010;23:465-95.
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Volume 21. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93-111. 22. Pettersen MD, Du W, Skeens ME, Humes RA. Regression equations for calculation of z Scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr 2008;21:922-34. 23. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 24. Shimizu M, Kario K. Review: role of the augmentation index in hypertension. Ther Adv Cardiovasc Dis 2008;2:25-35. 25. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588-605. 26. Bonetti P, Pfisterer M, Lerman A. Attenuation of digital reactive hyperemia in patients with early and advanced coronary artery disease. J Am Coll Cardiol 2005;45:407A. 27. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statist Med 1998;17:407-29. 28. Schubert U, M€ uller M, Edstedt Bonamy AK, Abdul-Khaliq H, Norman M. Aortic growth arrest after preterm birth: a lasting structural change of the vascular tree. J Dev Orig Health Dis 2011;2:218-25. 29. Chan PYL, Morris JM, Leslie GI, Kelly PJ, Gallery EDM. The long-term effects of prematurity and intrauterine growth restriction on cardiovascular, renal, and metabolic function. Int J Pediatr 2010;2010:1-10. 30. McEniery CM, Bolton CE, Fawke J, Hennessy E, Stocks J, Wilkinson IB, et al. Cardiovascular consequences of extreme prematurity: the EPICure study. J Hypertens 2011;29:1367-73. 31. Norman M. Low birthweight and the developing vascular tree: a systematic review. Acta Paediatr 2008;97:1165-72. 32. Sarkola T, Manlhiot C, Slorach C, Bradley TJ, Hui W, Mertens L, et al. Evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes. Arterioscler Thromb Vasc Biol 2012;32:2516-24. 33. Edstedt Bonamy AK, Bengtsson J, Nagy Z, De Keyzer H, Norman M. Preterm birth and maternal smoking in pregnancy are strong risk factors for aortic narrowing in adolescence. Acta Paediatr 2008;97:1080-5. 34. Aburawi EH, Malcus P, Thuring A, Fellman V, Pesonen E. Coronary flow in neonates with impaired intrauterine growth. J Am Soc Echocardiogr 2012;25:313-8. 35. Murotsuki JJ, Challis JRJ, Han VKV, Fraher LJL, Gagnon RR. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol Regul Integr Comp Physiol 1996;272:R201-7. 36. Armstrong AC, Gidding S, Gjesdal O, Wu C, Bluemke DA, Lima JAC. LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice. JACC Cardiovasc Imaging 2012;5:837-48.
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Additional members of the Victorian Infant Study Group include: Premature Infant Follow-Up Program at the Royal Women’s Hospital, Parkville, Australia: Catherine Callanan, RN, Noni Davis, Cinzia R. De Luca, BSc, PhD, Julianne Duff, FRACP, Esther Hutchinson, BSc (Hons), Elaine Kelly, MA, Marion McDonald, RN, FRACP, Carly Molloy, PhD, and Michelle Wilson-Ching, PhD; Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia: Peter Anderson, PhD, and Alice Burnett, PhD; Monash Newborn, Monash Medical Center, Melbourne, Australia: Elizabeth Carse, FRACP, Margaret P. Charlton, MEd Psych, and Marie Hayes, RN; Neonatal Services, Mercy Hospital for Women, Melbourne, Australia: Elaine Kelly, MA, Gillian Opie, FRACP, Andrew Watkins, FRACP, Amanda Williamson, BA, and Heather Woods, RN; Clinical Sciences, Murdoch Children’s Research Institute, and Royal Children’s Hospital, Parkville, Australia: Gehan Roberts, MPH, PhD, FRACP, and Colin Robertson, MD; School of Psychology, University of Birmingham, Birmingham, United Kingdom: Stephen Wood, PhD.
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Table II. Demographic and birth details by study participation Ex-preterm Gestational age, wk Antenatal corticosteroids Birthweight, g Birthweight z-score SGA (z-score < 2 SD) Male Smoking at 18 y of age Family history HT Controls Gestational age, wk Birthweight, g Birthweight z-score SGA Male Smoking at 18 y of age Family history HT
Participants
Nonparticipants
n = 109 26 1 78 (71.6%) 896 178 0.2 0.86 2 (1.8%) 59 (54.1%) 27 (24.8%) 54/78 (69.2%) n = 81 39 1 3398 437 0.04 0.9 0 31 (38.3%) 18 (22.2%) 35/60 (58.3%)
n = 116 26 1 82 (70.7%) 886 183 0.34 0.88 3 (2.6%) 54 (46.6%) 9 (7.8%) 18/34 (52.9%) n = 181 39 1 3373 443 0.06 0.9 1 (1%) 95 (52.5%) 17 (9.4%) 22/64 (34.4%)
P value .10 1.0* .67 .20 1.0* .29* .001* .13* .60 .67 .37 .50* .03* .005* .09*
HT, hypertension. Values are mean SD or n. *c2 test.
Table V. Significant between group sex differences Ex-preterm Females IVSd, mm IVSd z-score LV PWd, mm LV PWd z-score RWT Males IVSd, mm IVSd z-score LV PWd, mm LV PWd z-score RWT
n = 50 7.36 1.13 0.22 0.70 7.49 1.04 0.25 0.67 0.32 0.04 n = 59 7.98 1.35 0.05 0.65 8.19 1.17 0.47 0.81 0.33 0.05
Control n = 48 7.56 0.87 0.21 0.57 7.34 0.90 0.03 0.65 0.31 0.04 n = 33 8.97 1.14 0.47 0.70 8.88 0.89 0.68 0.51 0.34 0.04
P value .32 .98 .45 .10 .18 <.001 .007 .002 .14 .06
Mean difference (95% CI) 0.20 ( 0( 0.15 ( 0.22 ( 0.01 (
0.20, 0.61) 0.25, 0.26) 0.54, 0.24) 0.49, 0.04) 0.03, 0.01)
0.99 (0.47-1.52) 0.42 (0.12, 0.72) 0.69 (0.26, 1.12) 0.20 ( 0.07, 0.48) 0.02 ( 0, 0.04)
IVSd, interventricular septal dimension; PWd, posterior wall dimension; RWT, relative wall thickness. Values are mean SD.
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L
ow birthweight and prematurity predispose to higher cardiovascular morbidity and mortality in adulthood.1-4 Indeed, vascular abnormalities may be evident by adolescence or early adult life, including an elevated pulse wave velocity (PWV),5,6 increased carotid intima-media thickness (cIMT),6,7 aortic narrowing,5,8,9 and impaired microvascular func7,9,10 tion. More recently, increased left ventricle (LV) mass with increased LV wall thickness and reduced luminal diameter has been reported in ex-preterm young adults.11 Ex-preterm subjects are heterogeneous, however, as they may have in utero growth restriction (IUGR), be small for gestational age (SGA) or appropriate weight for gestational age (AGA) at birth, and also because prematurity can span moderately preterm (32-36 weeks’ gestation), very preterm (28-31 weeks’ gestation), and extremely preterm (<28 weeks’ gestation) categories. The latter category is increasingly relevant as survival of babies born extremely preterm has improved dramatically over recent years.12 Thus, studies in ex-preterm adolescents and adults born at varying gestations and with varying in utero growth impairment have suggested that increasing prematurity is associated with greater vascular dysfunction6,7 and LV mass.11 By contrast, evidence from small cohorts of extremely preterm but AGA infants and children suggests that, even though From the Heart Research, Murdoch Children’s blood pressures may be elevated,13 no differences exist between AGA exResearch Institute; Department of Cardiology, Royal 13 14 Children’s Hospital; Department of Pediatrics, preterm and control groups in LV mass index, PWV, or microvascular dilaUniversity of Melbourne; Developmental Imaging, tion.15 However, whether additional cardiovascular abnormalities emerge as Murdoch Children’s Research Institute; Research Office, Royal Women’s Hospital; and Department of extremely preterm subjects progress toward adulthood is unknown. Obstetrics and Gynecology, University of Melbourne, Parkville, Victoria, Australia The main aim of the study was to define longer-term cardiovascular sequelae *Additional members of the Victorian Infant Brain Study of being born extremely preterm, comparing results with term-born controls, Group is available at www.jpeds.com (Appendix). who have been followed since birth as part of the Victorian Infant Collaborative Supported by the National Health and Medical Research 1
2
3
4
5
6
AGA AIx BSA cIMT IUGR LV PWV SGA
Appropriate weight for gestational age Augmentation index Body surface area Carotid intima-media thickness In utero growth restriction Left ventricle Pulse wave velocity Small for gestational age
Council, Canberra, Australia (491246 to [to L.D., P. Anderson, S. Wood, C. Robertson, S. Hope, D. Hacking, J. Cheong]); Center for Clinical Research (Excellence Award 546519 [to L.D., P. Davis, T. Inder, P. Anderson, C. Kuschel, R. Hunt, J. Cheong, D. Hacking); Center of Research Excellence (1060733 to [L.D., P. Davis, P. Anderson, R. Hunt, J. Cheong, S. Jacobs, G. Roberts, A. Spittle, D. Thompson, J. Dawson]); the Victorian Government’s Operational Infrastructure Support Program (Post-graduate Scholarship to R.K.); and the Royal Children’s Hospital Foundation, Melbourne, Australia (Big W and RCH 1000). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.020
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Study.16 In addition, we aimed to assess the effect of IUGR on the cardiovascular measures within the extremely preterm cohort alone.
Methods After study approval from the institutional Human Research Ethics Committee and written informed consent, participants were recruited from the Victorian Infant Collaborative Study cohort, which included all extremely preterm (gestation <28 weeks) or low birthweight (<1000 g) survivors born in Victoria, Australia in 1991-1992.16 The original cohort was comprised of 298 preterm survivors and 262 control infants. Control infants were born in maternity hospitals housing neonatal intensive care units, had birthweights of >2499 g, were randomly selected from births on the due date of the preterm survivor, and were matched for sex. Of the original cohort, only a subset of 109 subjects born <28 weeks’ gestation and 81 control subjects were able to attend the Royal Children’s Hospital for anthropometric and blood pressure measurements, echocardiography, and vascular assessment at 18.0 0.9 (mean SD) years of age. Anthropometric and blood pressure data at 18 years from both cohorts have been reported elsewhere.17 All the measurements were performed in a single session by the same technologist who was unaware of subjects’ group classification. Presence of renal disease, diabetes mellitus, smoking status, and family history of hypertension were recorded after taking a clinical history. Subjects were asked to abstain from alcohol, tobacco, and caffeine for $24 hours, and were fasted for $6 hours prior to study. Body surface area (BSA) was calculated by the formula of Dubois and Dubois,18 with body mass index defined as weight (kg)/height (m)2. After 10 minutes of semirecumbent rest in a quiet darkened room, right brachial blood pressure was recorded in triplicate using a blood pressure cuff width that was greater than 40% of the upper arm circumference, with a digital oscillometric monitor (HEM 705-CP; Omron, Kyoto, Japan).19 Ambulatory blood pressure was measured for 24 hours using the Oscar 2 ambulatory blood pressure monitor (SunTech Medical Inc, Morrisville, North Carolina). Measurements were performed one-half hourly when awake, and hourly when asleep, and generated systolic, diastolic, and mean blood pressure values at each time point. Echocardiography (Vivid 7; GE Medical Systems, Horten, Norway) was performed in semirecumbent patients according to American Society of Echocardiography guidelines,20,21 using a 5 MHz transducer for cardiac and aortic sonography, and a 10 MHz linear probe for carotid imaging. Ascending aortic, left atrial, and LV diameters were obtained using Mmode and normalized by z-scores.22 To assess LV systolic function, fractional shortening was calculated from M-mode and ejection fraction with Simpson biplane method, and diastolic function was evaluated with transmitral Doppler velocities, isovolumic relaxation time, and tissue Doppler analysis. 2
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LV mass was indexed to BSA.23 Relative wall thickness was calculated as (LV posterior wall + interventricular septal dimensions)/LV end-diastolic dimension. Right common carotid and radial artery pressure waveforms were obtained with an applanation tonometer (SPT301 Transducer, Millar Instruments, Houston, Texas) interfaced to a SphygmoCor system (AtCor Medical, Sydney, Australia). The central aortic pressure profile was obtained by mathematical transformation of the radial signal and augmentation index (AIx) then derived after determination of the ascending limb inflection point.24 The carotid pulse-to-sternal notch and sternal notch-toright radial artery distances were measured to the nearest cm, with carotid-radial PWV calculated as carotid-to-right radial artery path-length divided by the difference between arrival time of the pressure wave foot at these two sites.25 The cIMT was measured offline in the right common carotid artery posterior arterial wall, 1 cm proximal to the carotid bulb,21 using wall-tracking software (EchoPAC, GE Vingmed Ultrasound, Norway). Microcirculatory responses were assessed using the EndoPAT system (Itamar Medical, Caesarea, Israel), with probes placed on the tips of both index fingers. After a period of equilibration, a left arm blood pressure cuff was inflated to 50 mm Hg above systolic pressure for 5 minutes, with reactive hyperaemia recorded after cuff deflation.26 Statistical Analyses Data were analyzed with SPSS (v 20; IBM Corp, Armonk, New York), with normality assessed using Levene’s test. Between-group data were compared with an independent Student t test for continuous normally distributed data and c2 analysis for categorical variables, with results presented as mean differences (95% CI). To detect if differences between groups were sex-specific, we ran regression models including an interaction term for sex and group; if the interaction term was significant, group differences were compared within each sex separately. To assess the associations of the cardiovascular measures with IUGR within the ex-preterm cohort, we regressed the various measures against the birthweight SD score, calculated relative to the British Growth Reference.27 With 109 preterm subjects and 81 controls, the study had 80% power to detect a mean difference between groups as small as 0.41 SD. Within the ex-preterm cohort alone, the study had 80% power to detect a correlation coefficient between continuous variables as small as 0.26.
Results As expected, although predominantly AGA, ex-preterm subjects were smaller at birth, with a trend toward lower birthweight z-scores (Table I). Only 2% of our pre-term study cohort were born SGA (birthweight z-score < 2 SD), with no SGA patients in the control group. At the time of the cardiovascular study, corrected age, weight, and body mass Kowalski et al
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Table I. Subject demographics and blood pressure variables At birth Gestational age, wk Birthweight, g Birthweight z-score Male SGA (z-score < 2 SD) Antenatal corticosteroids At study Corrected age, y Height, cm Weight, kg BSA, m2 BMI, kg/m2 Smoking at 18 y of age Family history HT HR, beats per min Brachial SBP, mm Hg Brachial DBP, mm Hg Brachial MBP, mm Hg Brachial PP, mm Hg Ambulatory blood pressure SBP 24 h, mm Hg DBP 24 h, mm Hg MBP 24 h, mm Hg
Ex-preterm (n = 109)
Control (n = 81)
P value
Mean difference (95% CI)
25.7 1 896 169 0.2 0.86 59 (54.1%) 2 (1.8%) 78 (71.6%)
39.1 1 3398 437 0.04 0.9 33 (40.7%) 0 (0.0%) 1 (1.2%)
<.001 <.001 .07 .08* .51* <.001*
13.4 (13.0, 13.7) 2502 (2400, 2604) 0.24 ( 0.02, 0.49)
17.9 0.8 166.7 9.8 64.5 14.9 1.7 0.2 23.3 5.1 27 (24.8%) 54/78 63 13 124 13 72 8 89 8 52 12 n = 91 131 13 71 8 91 9
18.1 0.9 170.3 8.1 66.9 13.7 1.8 0.2 23.0 3.9 18 (22.2%) 35/60 60 10 118 10 67 7 84 7 51 9 n = 71 127 13 68 8 88 9
.13 .007 .24 .05 .72 .73* .21* .14 .002 <.001 <.001 .67
0.2 ( 0.1, 0.4) 3.6 (1.0, 6.1) 2.1 ( 1.7, 6.5) 0.1 (0.0, 0.1) 0.2 ( 0.5, 1.1)
.15 .008 .02
3( 5( 5( 5( 1(
6, 1) 9, 2) 7, 3) 7, 3) 4, 2)
3 ( 7, 1) 3 ( 6, 1) 3 ( 6, 1)
BMI, body mass index; DBP, diastolic blood pressure; HT, hypertension; HR, heart rate; MBP, mean blood pressure; PP, pulse pressure; SBP, systolic blood pressure. Values are mean SD or n (%). *c2 test.
index were not different between groups, but ex-preterm subjects were shorter, and had a smaller BSA. No study subjects had structural heart disease, nor history of renal disease or diabetes, and there were no differences in smoking status or family history of hypertension. Ex-preterm subjects had higher brachial systolic, diastolic, and mean blood pressures, but there was no difference in pulse pressure. Ambulatory blood pressure results were available for 91 ex-preterms and 71 controls. Ex-preterm subjects had higher diastolic and mean blood pressures, but the systolic pressure was not significantly different. Compared with those from the inception study cohort who did not participate in this study, there was a higher rate of smoking at 18 years of age in both ex-preterm and control groups, and a lower percentage of males in participating controls, but otherwise there were no significant perinatal or demographic differences (Table II; available at www. jpeds.com). Although left atrial z-scores were similar, LV end-diastolic, LV end-systolic and ascending aortic z-scores, as well as indexed LV end-diastolic and end-systolic volumes, were smaller in ex-preterm subjects (Table III). LV posterior wall thickness and relative wall thickness were not different between groups, but in ex-preterm subjects, the interventricular septal thickness but not z-score was smaller, and absolute and indexed LV mass were lower. Compared with controls, stroke volume was lower in expreterm subjects, but LV fractional shortening, LV ejection fraction, and LV diastolic indices were preserved, with the exception of the LV E’ (early diastolic wave peak on tissue Doppler analysis) velocity, which was lower in the ex-
preterm group. The tricuspid regurgitant velocity and right ventricular isovolumic acceleration were greater in the expreterm group. Neither PWV, AIx, cIMT, nor reactive hyperaemia index differed between groups (Table IV). The only interaction terms for sex that were significant were for measures of ventricular wall thickness (interventricular septal dimension and its z-score, left ventricular posterior wall dimension and its z-score, and relative wall thickness). The differences between preterm and term subjects for these variables were largely found in males, and not females (Table V; available at www.jpeds.com). When adjusted for current size, there were no significant relationships between any cardiovascular measure and birthweight SD score, other than the peak systolic waves in the LV, septum, and right ventricle as assessed by tissue Doppler analysis, which displayed a weak positive relationship with birthweight z-score, even though no such relationship was evident with other measures of systolic function (Table VI).
Discussion A reduced ascending aortic diameter in ex-preterm adolescents was expected, as a decreased abdominal aortic diameter has been reported in AGA or SGA ex-preterm adolescent girls.5 Moreover, the smaller diameter of other major arteries, such as the brachial artery in adolescents10 and the common carotid artery in infants,28 suggests that a generalized growth impairment of systemic arterial vasculature accompanies preterm delivery. Despite finding smaller aortic diameters in our ex-preterm cohort, central AIx was similar between groups, a disparity
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Table III. Doppler echocardiographic data Ex-preterm (n = 109)
Control (n = 81)
P value
1.17 1.13 0.42 0.78 8.14 1.21 0.06 0.71 50.3 4.47 0.36 0.86 31.9 3.98 0.38 0.85 7.97 1.17 0.30 0.67 0.32 0.04 145 41 81 16 37 4 66 4 67 12 23 5 78 21 2.28 0.62 66 9 2.0 0.23 10.7 1.62 17.6 2.43 8.4 0.83 14.7 1.92 13.5 2.11 16.0 2.85 3.23 1.3 1.28 0.56 5.88 1.64 1.97 0.71
.95 .02 .02 .18 .007 .02 .003 .005 .57 .46 .93 .01 .02 .05 .09 <.001 <.001 .005 .38 .10 .003 .20 .04 .68 .24 .65 .29 1.0 .29 .10 .002
1.16 1.08 0.13 0.89 7.70 1.29 0.07 0.68 48.5 4.03 0.07 0.77 30.2 3.53 0.03 0.85 7.87 1.16 0.37 0.76 0.32 0.05 130 34 75 14 38 4 67 5 61 10 20 5 70 17 2.2 0.61 68 11 2.1 0.22 10.4 2.11 16.8 2.65 8.3 1.05 14.4 1.74 13.3 2.05 16.4 2.56 3.23 1.56 1.38 0.72 6.32 1.94 2.4 1.05
LA z-score AscAo z-score IVSd, mm IVSd z-score LV EDd, mm LV EDd z-score LV ESd, mm LV ESd z-score LV PWd, mm LV PWd z-score LV RWT LV mass, g LV mass index, g/m2 FS, % LVEF, % LV EDV/BSA (mL/m2) LV ESV/BSA (mL/m2) Stroke volume, mL MV E:A IVRT, ms TR velocity LV S’ wave LV E’ wave Septal S’ wave Septal E’ wave RV S’ wave RV E’ wave LV IVV LV IVA RV IVV RV IVA
Mean difference (95% CI) 0.01 ( 0.31, 0.33) 0.29 (0.05, 0.52) 0.44 (0.08, 0.80) 0.14 ( 0.06, 0.34) 1.73 (0.49, 2.98) 0.29 (0.05, 0.53) 1.69 (0.59, 2.79) 0.36 (0.11, 0.60) 0.17 ( 0.24, 0.43) 0.1 ( 0.28, 0.13) 0.01 ( 0.01, 0.01) 15 (4, 26) 6 (1, 10) 1 ( 2, 0) 1 ( 2, 0) 6 (3, 9) 3 (1, 4) 8 (2, 14) 0.08 ( 0.10, 0.26) 2 ( 5, 0) 0.1 ( 0.17, 0.03) 0.35 ( 0.19, 0.88) 0.78 (0.05, 1.51) 0.57 ( 0.21, 0.33) 0.32 ( 0.21, 0.86) 0.14 ( 0.47, 0.74) 0.43 ( 1.22, 0.37) 0 ( 0.43, 0.43) 0.10 ( 0.30, 0.09) 0.45 ( 0.98, 0.09) 0.43 ( 0.69, 0.16)
AscAo, ascending aorta; E’, early diastolic wave peak on tissue Doppler analysis; EDd, end-diastolic diameter; EDV, end-diastolic volume; ESd, end-systolic diameter; ESV, end-systolic volume; FS, fractional shortening; IVA, isovolumic acceleration; IVRT, isovolumic relaxation time; IVSd, interventricular septal dimension; IVV, isovolumic velocity; LA, left atrium; LVEF, LV ejection fraction; MV, mitral valve; PWd, posterior wall dimension; RV, right ventricle; RWT, relative wall thickness; S’, systolic wave peak on tissue Doppler analysis; TR, tricuspid regurgitation. Values are mean SD.
presumably related to AIx being a composite variable influenced both by arterial stiffness, which was not demonstrably different between groups in our cohort, and global wave reflection.24 The lack of a difference in AIx in our study population is similar to children born very preterm and AGA,29 but differs from the raised AIx reported in a mixed cohort of extremely preterm children, which had a higher proportion of SGA subjects.30 This is in accord with the observation that, in children born very preterm, AIx is higher in SGA than AGA,29 as well as the conclusion that preterm birth and IUGR produce different alterations in vascular growth patterns.31 Extremely preterm birth in our study was not associated with changes in vascular function. Thus, PWV values were similar to published population data,32 and accorded with
Table IV. Vascular function data
PWV, m/s AIx, % cIMT, mm RHI
Ex-preterm (n = 109)
Control (n = 81)
P value
5.6 1.0 9.8 17.9 0.43 0.05 2.01 0.57
5.7 0.9 8.7 16.8 0.43 0.03 2.10 0.56
.28 .67 .93 .32
RHI, reactive hyperemia index. Values are mean SD.
4
Mean difference (95% CI) 0.15 ( 1.1 ( 0.00 ( 0.09 (
0.12, 0.43) 6.2, 4.0) 0.01, 0.01) 0.09, 2.60)
the near-identical PWV observed in AGA children born very preterm or term.14 Large vessel structure assessed by cIMT was also no different, with values similar to those reported for normal adolescents.32 Furthermore, the normal endothelial function in ex-preterm adolescents agreed with the conclusions that brachial flow-mediated vasodilation was not different in young adolescents born AGA, and either very preterm or term,10 and that IUGR, rather than preterm birth, predisposes to endothelial dysfunction.10,31 Our blood pressure findings are similar to reports that both systolic and diastolic blood pressures are elevated in ex-preterm adolescents5,33 and young adults,6,11 and as we reported in our study of ambulatory blood pressure in the whole cohort of preterm subjects compared with controls at 18 years of age, where the changes in blood pressure between study groups were similar to the resting differences presented in this study, with the exception of the ambulatory systolic pressure, which likely reflects the smaller sample size.17 Nonetheless, longer term follow-up is warranted to establish whether this observed slight but significant blood pressure elevation in ex-preterm adolescents predisposes to development of hypertension in adulthood. In a recent study of young adults born prematurely, diastolic and systolic LV diameters were smaller, but LV wall thickness, relative wall thickness, and LV mass index were all higher than controls, with these findings interpreted as Kowalski et al
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Table VI. Linear relationships of blood pressure, echocardiographic, and vascular data with birthweight z-score in ex-preterm adolescents (n = 109) Regression coefficient* (95% CI) Brachial SBP, mm Hg Brachial DBP, mm Hg Brachial MBP, mm Hg Brachial PP, mm Hg AscAo z-score LV EDd, mm LV EDd z-score LV ESd, mm LV ESd, z-score LV IVSd, mm LV IVSd z-score LV PWd, mm LV PWd z-score LV mass, g LV mass index, g/m2 FS, % LVEF, % MV E:A IVRT, ms TR velocity LV S’ wave LV E’ wave Septal S’ wave Septal E’ wave RV S’ wave RV E’ wave LV IVV LV IVA RV IVV RV IVA PWV, m/s AIx, % cIMT, mm RHI
0.40 ( 2.51, 3.08) 0.72 ( 2.58, 1.14) 0.34 ( 2.19, 1.51) 1.12 ( 1.63, 3.87) 0.01 ( 1.91, 2.10) 0.72 ( 0.17, 1.61) 0.03 ( 0.14, 0.21) 0.45 ( 0.34, 1.24) 0.01 ( 0.08, 0.20) 0.25 ( 0.04, 0.53) 0.07 ( 0.09, 0.22) 0.26 (0.00, 0.51) 0.05 ( 0.12, 0.22) 8.88 (1.39, 16.36) 2.65 ( 0.54, 5.84) 0.08 ( 1.02, 0.85) 0.57 ( 0.52, 1.65) 0.10 ( 0.23, 0.04) 1.27 ( 1.23, 3.76) 0.03 ( 0.25, 0.08) 0.60 (0.14, 1.06) 0.05 ( 0.54, 0.64) 0.23 (0.00, 0.46) 0.05 ( 0.34, 0.44) 0.43 ( 0.02, 0.88) 0.13 ( 0.44, 0.70) 0.06 ( 0.30, 0.42) 0.11 ( 0.06, 0.28) 0.01 ( 0.46, 0.45) 0.07 ( 0.31, 0.18) 0.03 ( 0.20, 0.25) 0.30 ( 3.75, 4.34) 0.00 ( 0.01, 0.02) 0.03 ( 0.11, 0.16)
% variance explained
P value
0.1 0.6 0.1 0.6 0 2.4 0.1 1.2 0 2.7 0.7 3.5 0.4 4.9 2.5 0 1 1.8 1 1.1 5.9 0 3.6 0.1 3.3 0.2 0.1 1.7 0 0.3 0.1 0 0.01 0.1
.79 .44 .71 .42 .94 .11 .71 .26 .94 .09 .38 .05 .53 .02 .1 .86 .31 .17 .32 .31 .01 .87 .05 .81 .06 .66 .74 .20 .97 .58 .82 .88 .45 .71
*Change in cardiovascular variable per unit change in birthweight z-score.
evidence of accelerated cardiomyocyte hypertrophy during postnatal growth.11 By contrast, although LV cavity diameters were also smaller in our ex-preterm adolescents, LV wall thickness and mass were generally lower than in controls (Table III), implying an attenuation of postnatal LV growth. One possible basis for this difference relates to an effect of IUGR, as ex-preterm subjects in the study of Lewandowski et al11 were part of a mixed cohort, with 30% SGA and only 14% born extremely preterm. Indeed, IUGR appears to stimulate cardiac growth, as it resulted in an increase in LV mass index in term neonates,34 and LV wall thickness and mass were increased in late gestation fetal sheep following growth restriction produced by placental embolization.35 Thus, postnatal LV growth patterns after preterm birth may also be heterogeneous, and influenced by coexistent IUGR.31 A possible contribution of methodological differences also needs to be considered, as we used M-mode echocardiography to obtain LV mass, whereas Lewandowski et al11 used magnetic resonance imaging. Magnetic resonance imaging estimates of LV mass are more accurate as these do not involve assumptions about LV chamber geometry.36 Nonetheless, the use of different imaging modalities does not
explain the disparate findings of LV wall dimensions and relative wall thickness between our study (Table III) and that of Lewandowski et al.11 As in a mixed cohort of ex-preterm young adults,11 LV stroke volume was lower, but LV ejection fraction similar to control subjects; as in ex-preterm AGA children,13 LV transmitral velocity ratios were not different from control subjects, with only a minor reduction in LV E’ (early diastolic wave peak) tissue Doppler velocities, but no other tissue Doppler abnormalities to support significant reduction in diastolic function. Taken together, our findings suggest that LV systolic and diastolic function were preserved in expreterm and AGA adolescents, although we cannot exclude the possibility of differences in myocardial deformation patterns.11 Our study had several limitations. To allow equilibration of the physiological state and correlation of vascular and echocardiographic variables, the blood pressure was measured in a semirecumbent position, for which there are no normal blood pressure data published. The observed blood pressure differences between the 2 groups remain valid, however. We did not measure blood glucose or lipids, so any potential confounding effects of group differences between serum glucose and cholesterol levels on study results could not be assessed. Although there was insufficient power to classify the ex-preterm group by SGA/AGA status, there was no evidence of substantial relationships between growth restriction in utero and any of the cardiovascular variables, once adjusted for body size at adolescence. Finally, as no previous LV and vascular structural and functional assessments had been performed in our study groups, the effects of childhood growth and puberty on measured variables could not be specifically evaluated. Our findings suggest that, in the absence of coexistent growth impairment, adolescents born extremely preterm do not exhibit major cardiovascular abnormalities as they enter adult life. Continued follow-up is required to fully characterize the long-term cardiovascular sequelae of this cohort. n We thank Jane Koleff for acquisition of echocardiographic and vascular function data. Submitted for publication Oct 8, 2015; last revision received Dec 15, 2015; accepted Jan 6, 2016. Reprint requests: Remi R. Kowalski, MBBS, Department of Cardiology, The Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia. E-mail: [email protected]
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4. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938-41. 5. Bonamy AK, Bendito A, Martin H, Andolf E, Sedin G, Norman M. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls. Pediatr Res 2005;58:845-9. 6. Lazdam M, la Horra de A, Pitcher A, Mannie Z, Diesch J, Trevitt C, et al. Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism? Hypertension 2010;56:159-65. 7. Hovi P, Turanlahti M, Strang-Karlsson S, Wehkalampi K, Jarvenpaa AL, Eriksson JG, et al. Intima-media thickness and flow-mediated dilatation in the Helsinki study of very low birthweight adults. Pediatrics 2011;127: e304-11. 8. Bjarnegard N, Morsing E, Cinthio M, Lanne T, Brodszki J. Cardiovascular function in adulthood following intrauterine growth restriction with abnormal fetal blood flow. Ultrasound Obstet Gynecol 2013;41:177-84. 9. Brodszki J. Impaired vascular growth in late adolescence after intrauterine growth restriction. Circulation 2005;111:2623-8. 10. Singhal A, Kattenhorn M, Cole TJ, Deanfield J, Lucas A. Preterm birth, vascular function, and risk factors for atherosclerosis. Lancet 2001;358: 1159-60. 11. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, Francis J, et al. Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function. Circulation 2013;127:197-206. 12. Field D, Draper ES, Fenton A, Papiernik E, Zeitlin J, Blondel B, et al. Rates of very preterm birth in Europe and neonatal mortality rates. Arch Dis Child Fetal Neonatal Ed 2009;94:F253-6. 13. Morsing E, Liuba P, Fellman V, Marsal K, Brodszki J. Cardiovascular function in children born very preterm after intrauterine growth restriction with severely abnormal umbilical artery blood flow. Eur J Prev Cardiol 2014;21:1257-66. 14. Cheung YF. Relation of arterial stiffness with gestational age and birthweight. Arch Dis Child 2004;89:217-21. 15. Bonamy AKE, Martin H, J€ orneskog G, Norman M. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med 2007;262:635-42. 16. Doyle L. Outcome at 2 years of children 23-27 weeks’ gestation born in Victoria in 1991-92. The Victorian Infant Collaborative Study Group. J Paediatr Child Health 1997;33:161-5. 17. Roberts G, Lee KJ, Cheong JLY, Doyle LW. Higher ambulatory blood pressure at 18 years in adolescents born less than 28 weeks’ gestation in the 1990s compared with term controls. J Hypertens 2014;32:620-6. 18. Bois Du D, Bois Du EF. Clinical calorimetry: tenth paper a formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863. 19. O’Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001;322:531-6. 20. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010;23:465-95.
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Volume 21. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93-111. 22. Pettersen MD, Du W, Skeens ME, Humes RA. Regression equations for calculation of z Scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr 2008;21:922-34. 23. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 24. Shimizu M, Kario K. Review: role of the augmentation index in hypertension. Ther Adv Cardiovasc Dis 2008;2:25-35. 25. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588-605. 26. Bonetti P, Pfisterer M, Lerman A. Attenuation of digital reactive hyperemia in patients with early and advanced coronary artery disease. J Am Coll Cardiol 2005;45:407A. 27. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statist Med 1998;17:407-29. 28. Schubert U, M€ uller M, Edstedt Bonamy AK, Abdul-Khaliq H, Norman M. Aortic growth arrest after preterm birth: a lasting structural change of the vascular tree. J Dev Orig Health Dis 2011;2:218-25. 29. Chan PYL, Morris JM, Leslie GI, Kelly PJ, Gallery EDM. The long-term effects of prematurity and intrauterine growth restriction on cardiovascular, renal, and metabolic function. Int J Pediatr 2010;2010:1-10. 30. McEniery CM, Bolton CE, Fawke J, Hennessy E, Stocks J, Wilkinson IB, et al. Cardiovascular consequences of extreme prematurity: the EPICure study. J Hypertens 2011;29:1367-73. 31. Norman M. Low birthweight and the developing vascular tree: a systematic review. Acta Paediatr 2008;97:1165-72. 32. Sarkola T, Manlhiot C, Slorach C, Bradley TJ, Hui W, Mertens L, et al. Evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes. Arterioscler Thromb Vasc Biol 2012;32:2516-24. 33. Edstedt Bonamy AK, Bengtsson J, Nagy Z, De Keyzer H, Norman M. Preterm birth and maternal smoking in pregnancy are strong risk factors for aortic narrowing in adolescence. Acta Paediatr 2008;97:1080-5. 34. Aburawi EH, Malcus P, Thuring A, Fellman V, Pesonen E. Coronary flow in neonates with impaired intrauterine growth. J Am Soc Echocardiogr 2012;25:313-8. 35. Murotsuki JJ, Challis JRJ, Han VKV, Fraher LJL, Gagnon RR. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol Regul Integr Comp Physiol 1996;272:R201-7. 36. Armstrong AC, Gidding S, Gjesdal O, Wu C, Bluemke DA, Lima JAC. LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice. JACC Cardiovasc Imaging 2012;5:837-48.
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Additional members of the Victorian Infant Study Group include: Premature Infant Follow-Up Program at the Royal Women’s Hospital, Parkville, Australia: Catherine Callanan, RN, Noni Davis, Cinzia R. De Luca, BSc, PhD, Julianne Duff, FRACP, Esther Hutchinson, BSc (Hons), Elaine Kelly, MA, Marion McDonald, RN, FRACP, Carly Molloy, PhD, and Michelle Wilson-Ching, PhD; Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia: Peter Anderson, PhD, and Alice Burnett, PhD; Monash Newborn, Monash Medical Center, Melbourne, Australia: Elizabeth Carse, FRACP, Margaret P. Charlton, MEd Psych, and Marie Hayes, RN; Neonatal Services, Mercy Hospital for Women, Melbourne, Australia: Elaine Kelly, MA, Gillian Opie, FRACP, Andrew Watkins, FRACP, Amanda Williamson, BA, and Heather Woods, RN; Clinical Sciences, Murdoch Children’s Research Institute, and Royal Children’s Hospital, Parkville, Australia: Gehan Roberts, MPH, PhD, FRACP, and Colin Robertson, MD; School of Psychology, University of Birmingham, Birmingham, United Kingdom: Stephen Wood, PhD.
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Table II. Demographic and birth details by study participation Ex-preterm Gestational age, wk Antenatal corticosteroids Birthweight, g Birthweight z-score SGA (z-score < 2 SD) Male Smoking at 18 y of age Family history HT Controls Gestational age, wk Birthweight, g Birthweight z-score SGA Male Smoking at 18 y of age Family history HT
Participants
Nonparticipants
n = 109 26 1 78 (71.6%) 896 178 0.2 0.86 2 (1.8%) 59 (54.1%) 27 (24.8%) 54/78 (69.2%) n = 81 39 1 3398 437 0.04 0.9 0 31 (38.3%) 18 (22.2%) 35/60 (58.3%)
n = 116 26 1 82 (70.7%) 886 183 0.34 0.88 3 (2.6%) 54 (46.6%) 9 (7.8%) 18/34 (52.9%) n = 181 39 1 3373 443 0.06 0.9 1 (1%) 95 (52.5%) 17 (9.4%) 22/64 (34.4%)
P value .10 1.0* .67 .20 1.0* .29* .001* .13* .60 .67 .37 .50* .03* .005* .09*
HT, hypertension. Values are mean SD or n. *c2 test.
Table V. Significant between group sex differences Ex-preterm Females IVSd, mm IVSd z-score LV PWd, mm LV PWd z-score RWT Males IVSd, mm IVSd z-score LV PWd, mm LV PWd z-score RWT
n = 50 7.36 1.13 0.22 0.70 7.49 1.04 0.25 0.67 0.32 0.04 n = 59 7.98 1.35 0.05 0.65 8.19 1.17 0.47 0.81 0.33 0.05
Control n = 48 7.56 0.87 0.21 0.57 7.34 0.90 0.03 0.65 0.31 0.04 n = 33 8.97 1.14 0.47 0.70 8.88 0.89 0.68 0.51 0.34 0.04
P value .32 .98 .45 .10 .18 <.001 .007 .002 .14 .06
Mean difference (95% CI) 0.20 ( 0( 0.15 ( 0.22 ( 0.01 (
0.20, 0.61) 0.25, 0.26) 0.54, 0.24) 0.49, 0.04) 0.03, 0.01)
0.99 (0.47-1.52) 0.42 (0.12, 0.72) 0.69 (0.26, 1.12) 0.20 ( 0.07, 0.48) 0.02 ( 0, 0.04)
IVSd, interventricular septal dimension; PWd, posterior wall dimension; RWT, relative wall thickness. Values are mean SD.
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