Infants With Congenital Heart Disease at Risk of Early Atherosclerotic Disease

Abstract

Background

Aortic intima‐media thickness (aIMT) measurement is an established indicator of preclinical atherosclerosis. We aimed to describe the aIMT in infants with congenital heart disease undergoing cardiac surgery over the first year of life and explore its association with cardiopulmonary bypass, growth velocity, and a diagnosis of left heart obstruction.

Methods and Results

A prospective cohort study measuring mean and maximum aIMT preoperatively, at 3 months, and 1 year of age in neonates with congenital heart disease undergoing cardiac surgery. Twenty‐four infants with a median gestation of 39 weeks and a median birth weight of 3184 g were included. Sixteen (67%) infants had left outflow tract obstruction. Gestation correlated inversely with baseline mean aIMT (β=−0.027, P=0.018) and positively with the percentage of increase in mean and maximum aIMT between baseline and 3 months (β=17%, P=0.027 and β=15%, P=0.023). The presence of left outflow obstruction was significantly associated with increasing mean and maximum aIMT between baseline and 1 year (mean aIMT change: β=34%, P=0.017 and maximum aIMT change β=43%, P=0.001). Both subgroups of left heart obstruction and non‐left heart obstruction significantly changed over time (P=0.001 and P<0.001) but trends were not statistically different between both subgroups (P=0.21). Growth velocity and cardiopulmonary bypass were not associated with baseline or change in aIMT over the first year of life.

Conclusions

AIMT significantly increased over the first 3 months in our cohort of infants with repaired congenital heart disease. Increasing gestation was associated with decreasing aIMT at 3 months. Growth velocity and cardiopulmonary bypass were not associated with aIMT changes over the first year. Left heart obstruction was associated with a trend toward increased aIMT.

Most adult‐onset cardiovascular diseases and stroke are a subsequence of atherosclerosis. In patients with congenital heart disease (CHD), although atherosclerotic risks such as obesity, diabetes, and hypertension are still mainly implicated; it is not well established if certain risk factors related to their CHD can influence arterial wall changes and later atherosclerotic cardiovascular disease. ¹ , ² These risk factors may include the strong systemic inflammatory response that cardiopulmonary bypass stimulates; metabolic changes related to rapid catch‐up growth after caloric deprivation in the perioperative period; and specific types of CHD including conditions with obstruction of the left side of the heart and following cardiac surgery such as arterial switch operation, Ross procedure, and repair of anomalous coronary arteries. ³ , ⁴

Preclinical changes in cardiovascular function and structure, including arterial wall thickening and endothelial dysfunction consistent with early atherosclerosis, begin early in fetal life in the presence of intrauterine risk factors. ⁵ Ultrasound‐based measurement of aortic intima‐media thickness (aIMT) is considered a sensitive marker of preclinical atherosclerosis in infants and children because of the earlier development of atherosclerosis in aortic intima as identified on autopsies of infants, children, and young adults. ⁶ , ⁷

Our primary objectives were (1) to report longitudinal measurement of aIMT in children with CHD requiring neonatal cardiac surgery until the age of 12 months; (2) examine for an association of aIMT with growth velocity and cardiopulmonary bypass; and (3) examine the effect of left outflow tract narrowing or obstruction on aIMT trends.

METHODS

All study data and supporting materials are available on request from authors. This is a single‐center, prospective cohort study approved by the Human Research Ethics Committee (LNR/15/SCHN/247). Informed consents were obtained prospectively. Inclusion criteria were neonates ≥37 weeks gestation, with CHD, and admitted preoperatively for cardiac surgical intervention ≤28 days of age. Infants with aneuploidy and infants undergoing abdominal surgery, which precluded abdominal ultrasound, were excluded.

Maternal demographics and health risk factors including diabetes, body mass index ≥30 kg/m², hypertension, and smoking status were collected. Infant data included cardiac diagnosis and whether surgery was on cardiopulmonary bypass.

Weight and weight Z scores at birth; weight nadir (the lowest weight Z score) in the first 6 weeks postoperatively and weight Z scores at 3‐month follow‐up and 1‐year follow‐up were collected. AIMT was measured preoperatively, at follow‐up visits at 3 months, and at 1 year. Growth velocities were calculated from the lowest Z score point to 3 months and 1 year.

Measurement of the aIMT was attended using a previously verified method. ⁷ , ⁸ A 9 Hz linear transducer was used to image the distal‐most segment of the descending aorta for at least 3 high‐resolution loops, each capturing a minimum of 3 cardiac cycles. All scans were performed by one or other of 2 clinicians (A.M. or H.P.) trained in obtaining optimum images suitable for aIMT measurement.

AIMT measurements were calculated using edge‐detection analysis software, Carotid Analyzer for Research version 5.10.11 (MIA LLC, Iowa), as previously described. ⁸ The use of edge‐detection software for measurement of aIMT has superior intrareader and interreader reliability compared with manual sonographic caliper measurements. ⁹ The images were analyzed in random order by an experienced analyzer (M.H.) trained in the software and blinded to clinical history and chronological order of studies. Far wall mean aIMT and maximum aIMT were recorded for all studies, and average measurements were reported.

Statistical Analysis

Continuous data were summarized using means and SD if normally distributed, or medians and interquartile range otherwise. Categorical data were summarized using numbers and percentages. Univariate analysis of all variables was done using linear regression. Because of the small sample size of the baseline preoperative data set, multivariate regressions could not be performed. For all analyses, a P value <0.05 was considered statistically significant. All analysis was done using IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY: IBM Corp).

RESULTS

Twenty‐four infants were recruited. Their baseline characteristics are described in Table 1. Preoperative mean aIMT was 0.40 mm (±0.06 mm), preoperative maximum aIMT 0.47 mm (±0.09 mm), 3‐month mean aIMT 0.56 mm (±0.11 mm), 3‐month maximum aIMT 0.62 mm (±0.11 mm), 1‐year mean aIMT 0.52 mm (±0.08 mm) and 1‐year maximum aIMT 0.58 mm (±0.08 mm). Neonates who underwent cardiac surgery had a significant increase in aIMT at 3 months of age. (Figure).

Table 1.

Baseline Characteristics of Recruited Infants

Variable	n=24	Left heart obstruction n=16 (67%)	No left heart obstruction n=8 (33%)
Gestation wks, mean (SD)	39 (1)	39 (1)	38 (1)
Birth weight, g, mean (SD)	3184 (581)	3318 (632)	3041 (530)
Mean blood pressure, preoperative, mm Hg, mean (SD)	49 (6)	49 (6)	49 (5)
Maternal variables
Age, y, median (interquartile range)	32 (29–36)	31 (30–36)	29.5 (27.5–29.3)
Body mass index, kg/m2, median (interquartile range)	24 (21.5–27.5)	24 (23–27)	22.5 (21.5–33)
Smoking, n (%)	3 (13)	3 (19)	0
Hypertension, n (%)	3 (13)	3 (19)	0
Diabetes, n (%)	2 (8)	1 (6)	1 (13)
Race
White, n (%)	15 (63)	12 (75)	3 (38)
Cardiopulmonary bypass
Placement on cardiopulmonary bypass, n (%)	14 (58%)	8 (50)	6 (75)

Figure. Maximum aortic intima media thickness trends for infants with and without left heart obstruction (P=0.21).

aIMT indicates aortic intima media thickness.

Sixteen (67%) infants had left outflow tract obstruction, of whom 9 had coarctation of the aorta, 6 hypoplastic aortic arch, and 1 an interrupted aortic arch. The other infants had transposition of the great arteries (n=6), a large ventricular septal defect with rudimentary septum undergoing single ventricle palliation (n=1), and Ebstein's anomaly with pulmonary atresia (n=1). Fourteen infants (58%) underwent cardiopulmonary bypass for their surgical repair.

Table 2 describes the association between the infant and perioperative variables and mean and maximum aIMT measures (baseline and changes in baseline to 3 months and baseline to 1 year, respectively). Gestation correlated inversely with baseline mean aIMT (β=−0.027, P=0.018) and positively with the percentage of increase in mean and maximum aIMT between baseline and 3 months (β=17%, P=0.027 and β=15%, P=0.023). Maternal smoking, diabetes, and hypertension could not be tested owing to small numbers. Growth velocity expressed as change in weight Z scores from the weight nadir to 3 months and to 1 year was not associated with aIMT changes at 3 months or 1 year (Table 2).

Table 2.

Association Between Infant and Perioperative Variables and Mean and Maximum aIMT (Univariate Analysis)

	Baseline mean aIMT		Baseline Maximum aIMT		Mean aIMT change: Baseline to 3 months		Maximum aIMT change: Baseline to 3 months		Mean aIMT change: Baseline to 1 year		Maximum aIMT change: Baseline to 1 year
Variable	β, 95% CI	P value	β, 95% CI	P value	β, 95% CI	P value	β, 95% CI	P value	β, 95% CI	P value	β, 95% CI	P value
Birth weight Z score	−0.008 (−0.036 to 0.019)	0.535	−0.015 (−0.05 to 0.02)	0.434	−2.9 (−25.4 to 19.5)	0.789	−0.3 (−20.1 to 19.6)	0.979	6.8 (−7.8 to 21.4)	0.331	4.5 (−11.2 to 20.1)	0.547
Gestation	−0.027 (−0.05 to −0.01)	0.018	−0.03 (−0.06 to 0.01)	0.103	16.6 (2.1 to 31.1)	0.027	15 (2.3 to 27.7)	0.023	12.7 (0.4 to 25)	0.044	11.7 (−1.7 to 25.1)	0.081
Left heart obstruction	−0.05 (−0.1 to 0.003)	0.064	−0.09 (−0.16 to −0.016)	0.018	10 (−25.6 to 45.6)	0.563	13.3 (−17.7 to 44.4)	0.38	33.6 (7.1 to 60.2)	0.017	43.4 (20.2 to 66.6)	0.001
Cardiopulmonary bypass					−2.5 (−37.5 to 32.5)	0.883	−0.6 (−31.5 to 30.6)	0.97	−13.5 (−43.9 to 16.9)	0.355	−0.8 (−40.6 to 24.5)	0.603
Minimum weight Z score					−5.6 (−34.6 to 23.3)	0.688	−2.6 (−28.2 to 23)	0.834	8.6 (−8.9 to 26.1)	0.307	5.8 (−13 to 24.5)	0.517
Weight trajectory to 3 mo					3.4 (−20.9 to 27.7)	0.774	0.05 (−21.5 to 21.5)	0.996	−9.6 (−32.7 to 13.6)	0.385	−10.4 (−34.7 to 13.8)	0.368
Weight trajectory to 1 y					21.9 (−2 to 45.8)	0.069	16.5 (−5.4 to 38.4)	0.128	2.3 (−16.8 to 21.4)	0.798	2.2 (−17.8 to 22.1)	0.819

aIMT indicates aortic intima media thickness.

Cardiopulmonary bypass was not associated with aIMT changes at 3 months or 1 year. The presence of left outflow obstruction was significantly associated with increasing aIMT between baseline and 1 year (mean aIMT change: β=34%, P=0.017 and maximum aIMT change β=43%, P=0.001). Left heart obstruction was associated with trend toward persistence of increased aIMT between 3 months and 1 year (Figure). Both subgroups of left heart obstruction and non‐left heart obstruction significantly changed over time (P=0.001 and P<0.001) but trends were not statistically different between both subgroups (P=0.21) (Figure).

DISCUSSION

We describe the changes in aIMT over the first year of life in newborn infants undergoing cardiac surgery. The trend toward persistence of aIMT increase in left heart obstruction needs further research as a possible early indicator of vasculopathy. Growth velocity and cardiopulmonary bypass were not found to be associated with aIMT changes over the first year of life.

These aIMT trends in the first year of life following cardiac surgery may be capturing important early dynamic vascular changes in the aorta. All infants had a significant increase in aIMT between baseline and 3 months. This may be related to an exposure leading to the transient increase, such as surgical stress or inflammation, metabolic state related to reduced caloric intake or to a catabolic state, or some other risk. Infants with left heart obstruction showed a trend toward persistent increase in aIMT at 1 year. This raises questions about possible systemic vascular disease rather than a focal isthmus mechanical abnormality or abnormal aortic arch.

Left outflow tract obstruction, and particularly coarctation of the aorta, have been studied to determine the underlying mechanism of the persisting association with hypertension and coronary artery disease, even when early repair is achieved. In aortic stenosis, left ventricular hypertrophy is believed to be the underlying cause for cardiovascular morbidity, whereas in coarctation of the aorta, systemic hypertension was considered the main underlying cause for this association in repaired coarctation. In the past 2 decades, studies on neonates with repaired coarctation measuring aortic wall stiffness and distensibility found impaired elastic properties of the ascending aorta, supporting the assumption that coarctation was not only a localized aortic isthmus abnormality but also a systemic vascular disease of the precoarctation aorta. ¹⁰ , ¹¹ Although some earlier studies found the incidence of hypertension was higher in late coarctation repair, ¹² recent studies show a strong association between coarctation and risk of hypertension and coronary artery disease ¹³ and that elastic properties of the ascending aorta were abnormal even in newborns who underwent early repair, suggesting that this increased risk was related to the abnormal prestenotic aortic vascular bed. ¹⁰ , ¹¹

The different aIMT trend at age 12 months observed in our small cohort with left heart obstruction may relate to the hypothesis that the vascular bed further distally in the abdominal aorta may also be abnormal in patients with left heart obstruction such as coarctation of the aorta and hypoplastic aortic arch. This may be part of a wider aortopathy or vasculopath, and may be an underlying cause for the prevalence of hypertension and the increased risk of cardiovascular disease in this group of patients.

This study revealed a relationship between baseline aIMT and gestation. Despite all study patients being term infants between 37 and 41 weeks gestation, there was a statistical trend toward aIMT reduction as gestation advanced. This relationship is potentially true, but the magnitude was larger than reported in other studies, and it may be related to the small sample size.

Previous studies showed a relationship between birth small for gestational age and increased aIMT. This effect was also found in fetal studies suggesting the early onset of aIMT thickening occurs with in utero growth deceleration. ¹⁴ Large for gestation birthweight has also been associated with increased aIMT. ¹⁵ Our study showed no association between baseline aIMT and birthweight.

Infants undergoing cardiac surgery can develop growth failure and require calorie supplementation and enteral tube feeds. Rapid postnatal weight gain has been linked to insulin resistance, obesity, atherosclerosis, and metabolic syndrome. We hypothesized that rapid catch‐up growth measured by growth velocity may be associated with aIMT over the first year of life; however, no such association was discovered. It is possible that our follow‐up was not long enough, or our small sample size limited our capability to detect such an association.

Cardiopulmonary bypass stimulates a strong systemic inflammatory response, particularly in younger patients. As bypass inflammation is believed to be linked to increased risk of morbidity, some studies have tried to correlate the extent of inflammatory response with clinical outcomes, to provide risk stratification in this group of patients. We hypothesized that cardiopulmonary bypass might be an inflammatory trigger for aIMT increase. In our cohort, we did not find an association between cardiopulmonary bypass and aIMT changes at 3 months or 1 year.

To our knowledge, this is the first cohort of infants with CHD monitored for aIMT changes in infancy following cardiac surgery. Our study demonstrated that aIMT measurement in infants with CHD is feasible and reproducible in both intensive care and clinic settings and may have a role as a prognostic biomarker to improve risk stratification in children with CHD.

Although measurement of aIMT has so far been limited to research, it has growing potential as a prognostic biomarker improving risk stratification and identifying infants with CHD who may be at higher risk of ischaemic heart disease. Maximum aIMT is likely to have a more prognostic value than mean aIMT, given the natural progression of atherosclerosis and the focal thickening early in the disease process.

Limitations in our study were the sample size. Recruitment was obtained on arrival into the neonatal intensive care before surgery, which is usually a stressful period for parents. This meant consent was often difficult to achieve and limited our recruitment. The originally planned follow‐up to 3 years was not achieved because of COVID‐19 pandemic restrictions, and hence the follow‐up was revised to 1 year. although preoperative aIMT measurements were comparable to published aIMT values in term infants, it is important to note that there are still no standardized reference data for normal ranges. There may be variance secondary to different ultrasound equipment, including transducer and software, edge‐wise detection software, and operator‐dependent variances. This is in addition to the heterogeneity of the study populations across the different studies in the literature and the predominantly small sample sizes. Our subgroup with no left heart obstruction was small but its aIMT trend was used as a comparator as originally intended in our study. A larger sample size may have provided higher power to show significant difference between the subgroups.

Children with CHD are at high risk of early cardiovascular disease and need long‐term surveillance to further develop our understanding of their risk factors and their pathological processes. Recommendations so far have included blood pressure monitoring from before the age of 3, reducing exposure to smoking and development of obesity, low threshold for the use of hypotensors, and promoting exercise. ⁴ Studies like ours, but with larger cohorts, are needed in infants with CHD to investigate the role of aIMT in clinical practice to identify at‐risk infants. This can present opportunities for early intervention such as the studied beneficial effect of omega‐3 supplementation on aIMT trends in high‐risk infants.

CONCLUSIONS

AIMT significantly increased over the first 3 months in our cohort of infants with repaired CHD. Increasing gestation was associated with decreasing aIMT at 3 months. Growth velocity and cardiopulmonary bypass were not associated with aIMT changes over the first year. Left heart obstruction was associated with a trend toward increased aIMT.

Sources of Funding

None.

Disclosures

None.