Famine Exposure During Early Life Increased the Risk of Ascending Aorta Dilatation in Adults


 Background: The relationship between malnutrition and ascending aorta dilatation (AAD) is still unclear. Therefore, the aim of this study was to examine the association of exposure to the Chinese famine during early life with AAD in adulthood. Methods: We investigated data of 2598 adults born between 1952 and 1964 from Guangdong, China. All enrolled subjects were divided into five groups: no exposed, fetal exposed, early, mid and late childhood exposed. AAD was assessed by cardiac ultrasound. Multivariate logistic regression and interaction tests were used to estimate the odds ratio (OR) and confidence interval (CI) between famine exposure and AAD. Results: There were 2598 (943 male, mean age 59.1 ± 3.65 years) participants were enrolled, among them consist of 270 (10.4%) subjects with AAD. We found that famine exposure (OR=2.266, 95% CI: 1.477, 3.477, P=0.013), age, smoking, hypertension, elevated SBP, elevated BMI was an independent risk factor for AAD. In addition, compared with no exposed group, the adjusted ORs for AAD widening from fetal-exposed, early, mid to late childhood exposed were 1.374 (95% CI: 0.794, 2.364, P=0.251), 1.976 (95% CI: 1.243, 3.181, P=0.004), 1.929 (95% CI: 1.237, 3.058, P=0.004) and 2.227 (95% CI: 1.433, 3.524, P<0.001), respectively. Stratified analysis showed that the effect of famine exposure on AAD was more pronounced in female, smokers, BMI ≥24 kg/m2 and hypertensive patients. Conclusions: We observed that exposure to famine during early life was an independent risk factor for AAD in adulthood; this effect was not modified by gender, BMI, smoking, hypertension and diabetes.


Introduction
Thoracic aortic aneurysms rupture and dissection are one of the most devastating cardiovascular diseases (CVD) of the aorta vascular diseases, and these diseases are often accompanied by high mortality despite signi cant improvements in diagnostic imaging, interventional therapy and surgical techniques [1]. It has been showed that aortic root diameter increased or ascending aorta dilatation (AAD) was one of the main risk factor for thoracic aortic dissection and rupture [2]. The measurement of aortic diameters could play a vital role in the clinical evaluation and management of aorta related diseases [3,4]. At present, AAD was not a rare disease; it has been found that the incidence of European and American general population was 3.5% -13% [5,6]. AAD in pediatric primary with systemic hypertension was approximately 2.8% [7], in children with chronic kidney disease was 6% [8]. The prevalence of AAD in middle-aged and aged Chinese population was about 10.6% [9]. Although cardiovascular risk factors such as hypertension, smoking and obesity are associated with AAD, unstill now, the mechanism of AAD is still unclear. In recent years, the relationship between nutrition and cardiovascular diseases has received more and more attention. It has been shown that nutritional status was closely related to peripheral vascular diseases [10,11], such as cervical artery dissection [12]. In addition, more and more studies have also demonstrated that exposure to famine in early life was signi cantly associated with many cardiovascular metabolic diseases, such as diabetes [13], obesity [14], hypertension [15], coronary heart disease [16] and dyslipidemia [17]. Furthermore, recent a study indicated that AAD did occur early in the course of chronic kidney disease with malnutrition Children and associated with markers of poor nutrition, suggesting nutritional status may be related to AAD [8]. However, currently, there were very limited studies on famine exposure and AAD, and in order to de ne the knowledge gap between famine exposure and AAD. Therefore, the aim of the present study was to explore the relationship between famine exposure during early life and AAD in adulthood, and further analyze whether this effect can be modi ed by other cardiovascular risk factors including gender, hypertension, diabetes, smoking and overweight/obesity.

Study subjects
The data used in the current study were obtained from the samples from the Early Screening and Comprehensive Intervention Program for High Risk Population of CVD in Guangdong province, China. The Early Screening and Comprehensive Intervention Program for High Risk Population of CVD was a population-centred national screening initiative to detect populations at high risk of CVD in all 31 provinces in mainland China [18]. There were total of 10984 participants completed the screening in Guangdong province between 1 January 2017 and 31 December 2018.Among them aged 35 to 75 years and who completed the evaluation of the diameter of the ascending aorta (AAO) were included. Subjects who was missing AAO inner diameter data, and AAO inner diameter≥45mm was excluded. Finally, a total of 2598 subjects were enrolled for analysis. The research ow chart was shown in Figure 1. The protocol of the present study has been approved by the Ethics Committee at the Institute of Guangdong Provincial People's Hospital (No.GDREC2016438H (R2)) and complied with the principles of the Declaration of Helsinki. Informed written consent was obtained from all participants before enrolled in this study.

Ascending aorta assessment
All recordings of cardiac ultrasound examination were by using Vivid-S6 (GE Medical System, Milwaukee, Wisconsin, USA) interfaced with a 2.5-3.5 MHz phased-array probe. AAO dimensions were measured using two-dimensional echocardiography, the detailed measurement method was described previously [22]. In brie y, aortic root diameter was measured at the sinus level and sinotubular junction, and the AAO inner diameter was measured from a parasternal long axis view, as the maximal distance between the two leading edges in accordance with the American Society of Echocardiography guidelines [23]. AAD was de ned as an inner diameter of aortic root inner diameter ≥ 35 mm [24].

Covariates
A face-to-face structured questionnaire was performed to collect socio-demographic (including age, birth data, race, income, education level, census and marriage) and lifestyle (including smoking, drinking, physical activity and diet) data by well-trained study workers at baseline. Chronic diseases (such as hypertension and diabetes) and drugs currently in using (such as glucose lowering, antihypertensive and lipid-lowering drugs) were also collected. At baseline, laboratory tests mainly include fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Body weight, standing height, blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) were measured through standard processes. Body mass index (BMI) was calculated based on the formula: weight (kilograms) divided by height (meters squared). Diabetes was de ned as FBG ≥126 mg/dl or self-report or taking glucose lowering drugs [25]. Hypertension was de ned as SBP/DBP≥140/90mmHg or self-report or taking antihypertensive drugs [26].

Statistical analysis
All categorical variables were presented as number or percentage, and continuous variables as mean ± standard deviation. Differences in basic characteristics across famine exposure and AAD were compared by one-way analysis of variance (ANOVA), Kruskal-Wallis tests or Chi-Squared tests, where appropriate. Univariate and multivariate logistic regression was used to explore the correlation between famine exposure and AAD, and crude and adjusted odds ratio (OR) and con dence interval (CI) were calculated. In univariate analysis, variables with P < 0.1 were included in multivariate for further analysis, and traditional cardiovascular risk factors were also included. Adjusted covariates included gender, education and marital status, income, smoking status, drinking status, intake of vegetables and meat, physical activity, hypertension, diabetes, heart rate, systolic and diastolic blood pressure, fasting blood glucose, BMI, TG, TC, HDL-C, LDL-C, taking hypoglycemic, antihypertensive and lipid-lowering drugs. In addition, the collinearity between age and famine exposure status was evaluated, and a variance in ation factor greater than 10 was de ned as signi cant collinearity then this collinearity variable was not included in the multivariate adjustment model. Strati ed analyses were performed to evaluate whether the relationships between famine exposure and AAD would be modi ed by potential confounders, including gender, BMI, smoking, hypertension and diabetes. Interaction tests were estimated by including the multiplicative strati ed variables in the multivariate models. A 2-sided P < 0.05 was considered statistically signi cant. All statistical analyses were performed using R version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results
The characteristics of participants Basic characteristics of the 2598 participants by whether the AAD was presented in Table 1. Of the all the 2598 subjects, there were 943 (36.3%) male population, and the mean age was 59.1 ± 3.65 years. Compared to no AAD group, those in the AAD group were older, more likely to be smokers and drinkers, to be with hypertension, have higher SBP, DBP, BMI, TC, LDL-C and lower HDL-C. In addition, there was a greater proportion of exposed famine in AAD group compared with those without AAD (86.7%vs.76.1%, P=0.003).
Associations between famine exposure and ascending aorta dilatation As shown in Table 3, univariate logistic regression analysis demonstrated that age, education level, income, smoking, vegetable intake < 3 days per week, hypertension, SBP, BMI, HDL-C and famine exposure were signi cantly related to AAD, further multivariate logistic regression indicated that famine exposure (OR=2.266, 95% CI: 1.477, 3.477, P=0.013), age, smoking, hypertension, elevated SBP, elevated BMI was still an independent risk factor for AAD, and HDL-C was inversely related to AAD.
In addition, when famine exposure was further subdivided into non-exposed, fetal exposed, early-childhood, mid-childhood and late-childhood exposed group. Table 4 demonstrated the associations between famine exposure in early life and AAD, as the non-exposed group reference, the crude ORs with 95% CI for widening of AAD in fetal, early, mid and late childhood exposed were 1.179 (95% CI: 0.701,1.967, P=0.527),

Strati ed analyses
Strati ed analyses of famine exposure and AAD by selected factors were shown in Tables 5. We observed that childhood exposure to famine at any stage, it appears that there was a stronger risk of AAD in female, BMI ≥24 kg/m 2 , smokers, hypertensive patients and non-diabetes subjects. However, we also found that famine exposure in fetal period has no obvious relationship with AAD in adulthood. In addition, no statistically signi cant multiplicative effect modi cations were found among the strata factors including gender, BMI, smoking, hypertension and diabetes (all Pinteraction > 0.05).

Discussion
To explore the risk factors associated with AAD has important clinical signi cance. We found age, smoking, hypertension, SBP, BMI and HDL-C was closely related to AAD. In addition, this study was the rst time to found that exposure to famine in childhood may signi cantly increase the risk of AAD in adulthood, and this effect will not be modi ed by other cardiovascular risk factors, such as smoking, hypertension and diabetes. AAD often appears asymptomatic, but once ruptured it often lead to serious outcomes. Our research showed that older age, smoking, elevated SBP and increased BMI were independent risk factors for AAD, but HDL-C was negatively correlated with AAD. Our results were consistent with previous researches [27][28][29][30]. In addition, in this study, famine exposure during childhood was found to be an independent risk factor for AAD in adulthood after some potential confounding factors were adjusted. Famine exposure was usually accompanied by a lack of nutrient intake, such as protein, vitamins, and trace elements. Demir, et al [31] found that vitamin D de ciency was an independent factor for aortic dilatation. Adam and his team discovered the concentration of Copper and Zinc was signi cant associated with the size of the aneurysmal enlargement in the wall of the abdominal aortic aneurysm [32]. In addition, although there was no research has speci cally evaluated the relationship between Chinese early life famine exposure and AAD in adulthood, we further found that there was a stronger risk of AAD in female, BMI ≥24 kg/m 2 , smokers, hypertensive patients, and this effect has not been adjusted by the above traditional risk factors for AAD. This suggested that prevention of AAD should pay attention to nutrition status run through the entire life process from early life, and different population may need different nutritional support.
The mechanisms of the relationship between famine exposure and AAD remain unclear, but there have been several possibilities. First of all, subjects who survived from famine may develop compensatory nutrition or nutritional catch-up growth, which may lead to over-nutrition, and further lead to overweight or obesity. It has been found that obesity was independently related to AAD [33]. Second, the Dutch famine study revealed that those exposed to famine in early gestation could increase stress responsiveness [34]. AAD was considered as a disorder of oxidative stress, and basic research indicated that oxidative stress played an important role in thoracic aortic aneurysms [35]. Third, exposure to famine during early life was associated with increased risks of obesity in adulthood [36], and obesity was signi cantly linked with increased visceral, perivascular, and epicardial adipose tissue [37]. A previous study demonstrated that increased epicardial adipose tissue thickness was correlated with AAD [38]. Fourth, AAD was a chronic in ammatory disorder disease; its main feature was the local weakening and dilatation of the aortic wall [1] . Destructive remodeling of the extracellular matrix and endothelial dysfunction played a vital in AAD [39,40]. Based on animal and human studies, low birthweight babies and nutrient de ciency were likely to have endothelial dysfunction, less vascular elastin, increased sympathetic tone and liver-derived dyslipidemias [41,42].In addition, increased sympathetic tone was commonly associated with hypertension in animal models of both under nutritional and over nutritional states [43]. It was now generally accepted that exposure to famine in early life was closely related to adult hypertension [44], and that hypertension was an independent risk factor for AAD [45]. The mechanism of AAD is unclear. Therefore, further research is required to investigate the correlation between famine exposure and AAD.
The present study has several strengths. First, to our best knowledge, it was the rst study to investigate the relationship between famine exposure in early life and AAD in adulthood among Chinese population. Second, this study adjusted as many as possible risk factors related to the occurrence of AAD. However, some potential limitations should also be noted. First, this study did not collect birth weight and the severity of famine. These confounding factors have a certain impact on the results of the study. Second, it was a cross-sectional study, and the study population cannot represent the entire Chinese population. Third, some baseline variables, such as disease history and medication history come from self-reporting, so there may be a recall bias. Fourth, since children with poor health when exposed to famine during early life may have partially died, and the present study was to analyze the population that was still alive, so the impact of famine may be underestimated. Fifth, this study did not collect hematological markers related to nutritional status, nor did conduct quantitative and qualitative assessment of early nutrition. Sixth, the high collinearity between age and exposure group which could be potentially confounding the effect of famine exposure on AAD. In addition, the speci c start and end time of famine in China was not clear, so the grouping according to the date of birth may be different from the actual famine exposure. Finally, although the study group based on birth data, and the birth data was related to age, the possibility of residual confounding due to age differences could not be completely excluded.

Conclusions
In conclusion, the key ndings of the current study revealed that famine exposure in childhood was closely related to AAD in adulthood, but exposure in the fetal period has nothing to do with it. Famine exposure in childhood was an independent risk factor for AAD in adult. When exposed to famine during early life, subjects who were female, BMI ≥24 kg/m 2 , smokers, and to be with hypertension, may have a higher risk of AAD. The effect of exposure to famine on AAD will not be adjusted by other risk factors, including BMI, gender, smoking, hypertension and diabetes. These ndings are needed to be con rmed by further large-scale prospective studies.

Availability of data and materials
The dataset used and analyzed during the current study is available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The protocol of the present study has been approved by the Ethics Committee at the Institute of Guangdong Provincial People's Hospital (No.GDREC2016438H (R2)) and complied with the principles of the Declaration of Helsinki. Informed written consents were obtained from all participants before data collection.

Consent for publication
Not Applicable.

Con ict of interest
The authors declare that they have no con ict of interest. Data are presented as mean ± standard deviation or percentage.
AAO: ascending aorta; AAD: ascending aorta dilatation; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; BMI body mass index. Baseline characteristics among different famine exposure groups Overall Non-exposed Fetal exposed Early-childhood exposed Mid-childhood exposed Late childhood exposed OR odds ratio, CI con dence interval. OR odds ratio, CI con dence interval, VIF variance in ation factor.
Model 1with no variable was adjusted.
Model 2 with gender, education and marital status, income, smoking status, drinking status, intake of vegetables and meat, physical activity, hypertension, diabetes, systolic and diastolic blood pressure, fasting blood glucose, BMI, TG,TC, HDL-C, LDL-C, heart rate, taking hypoglycemic, antihypertensive and lipid-lowering drugs were adjusted. Table 5.
Subgroup analysis among different famine exposure groups Subgroup Nonexposed Fetal exposed Early-childhood exposed Mid-childhood exposed Late childhood exposed OR odds ratio, CI con dence interval, BMI body mass index.