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Research ArticleIntegrative Cardiovascular Physiology and Pathophysiology

Sex differences in cardiovascular disease and dysregulation in Down syndrome

Published Online:23 Mar 2023https://doi.org/10.1152/ajpheart.00544.2022

Abstract

This meta-analysis, which consisted of a scoping review and retrospective medical record review, is focused on potential sex differences in cardiovascular diseases in patients with Down syndrome. We limited our review to peer-reviewed, primary articles in the English language, in the PubMed and Web of Science databases from 1965 to 2021. Guidelines for scoping reviews were followed throughout the process. Four categorical domains were identified and searched using additional keywords: 1) congenital heart disease, 2) baseline physiology and risk factors, 3) heart disease and hypertension, and 4) stroke and cerebrovascular disease. Articles were included if they reported male and female distinct data, participants with Down syndrome, and one of our keywords. The retrospective medical record review was completed using 75 participating health care organizations to identify the incidence of congenital and cardiovascular diseases and to quantify cardiovascular risk factors in male and female patients. Female patients with Down syndrome are at higher risk of hypertension, ischemic heart disease, and cerebrovascular disease. The risk of congenital heart disease is higher in males with Down syndrome at all ages included in our analyses. Some of the male-to-female sex differences in cardiovascular disease risk in the general patient population are not present, or reversed in the Down syndrome population. This information should be considered for future investigations and ongoing patient care.

NEW & NOTEWORTHY In patients with Down syndrome (DS), CHD is the leading cause of death <20 yr old and cardiovascular disease is a leading cause of death in individuals >20 yr old. Men with DS live longer than women. It is unknown if sex differences are present in cardiovascular disease and dysregulation in DS across the lifespan. We observed higher risk of hypertension, ischemic heart disease, and cerebrovascular disease in females and a higher risk of CHD in males with DS.

INTRODUCTION

Individuals with Down syndrome (DS) are born with intellectual disability, typically because of triplication of the 21st chromosome and associated genes, but DS can also occur from translocation of the same chromosome. Fortunately, life expectancy has nearly doubled in individuals with DS, to a median age of 61.1 yr for men and 57.8 yr for women (1). It is now critically important to understand how individuals with DS will age, and whether risk factors that are predictive of cardiovascular disease in the general population are similarly predictive of cardiovascular disease risk in DS.

Congenital heart disease is the leading cause of death in patients with DS <20 yr old and cardiovascular disease is a leading cause of death in DS individuals >20 yr old (2). In the general population, there are strong sex differences in congenital heart disease risk (3). Male infants are at higher risk of hypoplastic left heart syndrome, aortic stenosis and coarctation, transposition of the great vessels, and double outlet right ventricle, whereas female infants are at a higher risk of patent ductus arteriosus, atrial septal defect, and pulmonary artery stenosis and atresia (3). Adult men are at higher risk of cardiovascular disease at an earlier age (4), but overall cardiovascular mortality is higher in women (5). There are sex-dependent patterns in the survival of individuals with DS that indicate that we should be cautious in extrapolating data from the general population to DS. In contrast to the general population where overall survival is poorer in men, the median lifespan is 3.3 yr longer in men with DS, compared with their female counterparts (6).

Given that congenital heart disease and cardiovascular disease are among the leading causes of death in the DS population, it is reasonable to hypothesize that sex differences may underpin some of the differences in lifespan. To date, there have been limited reports of sex differences in congenital heart disease, and no comprehensive reports focusing on sex differences in other cardiovascular diseases (7–10). We addressed this issue in two ways. First, we completed a scoping review of the literature. Second, we performed a retrospective medical records analysis of the population of patients with DS at 75 participating health care organizations to determine if sex differences exist in congenital heart and cardiovascular disease, cerebrovascular disease, and cardiovascular risk factors, relative to the general patient population.

METHODS

Scoping Review of the Literature

A scoping review was conducted in June 2021 with the overarching research question “Are there reported sex differences for congenital heart disease, cardiovascular physiology and risk factors, cardiovascular disease, and cerebrovascular disease in DS?” Recommendations for a scoping review were followed as described by Munn et al. (11) (Supplemental Table S1). Only primary, peer-reviewed research articles in English published between 1965 and 2021 were included in the final results. Case studies and reviews were excluded. The population investigated was individuals with DS from any setting (hospital, general practice, general population). The comparator was either a control group versus DS including males and females, or males and females with DS. The outcome was any cardiovascular measure reported in the study that fell within one of four categorical domains—congenital heart disease, differences in baseline physiology and risk factors, cardiovascular disease, and cerebrovascular disease. Search terms were added when appropriate to align with the medical records review. An exclusion term was added to eliminate studies performed only in animals.

To minimize bias (12), two investigators performed independent searches in PubMed and Web of Science across these four domain categories using preestablished search terms (Fig. 1; L.D.M.F. and Y.P.). The searches from each investigator were exported into EndNote and the duplicates were removed. If an article was repeated in more than one domain after the search, coauthors voted to determine the domain of best fit. When there were articles that had parameters fitting more than one domain (13, 14), the data were separated and listed in multiple domains. For example, if an article contained blood pressure and congenital heart disease data, this information was separated across two domain categories. Each article was reviewed by the senior authors (M.L.B. and L.R.D.) and assessed for inclusion/exclusion in our study (Fig. 2). The main outcomes were distilled from the results section of each article, not the conclusions of the published authors. Statistical outcomes were used from the publications and clinical relevance addressed throughout the results and discussion of this text. Many articles were included in the original search since they included both males and females in data collection. However, papers were excluded by the authors if they did not list data for men and women separately, and not simply in aggregate. In Fig. 2, these instances are listed as “removed X without mention of (potential) male/female differences.” Lastly, the articles were summarized to show sex comparisons in Table 1.

Figure 1.

Figure 1.Diagram depicting the search terms included in the scoping literature search process. Searches of PubMed and Web of Science were completed in June 2021 to evaluate potential sex differences in 4 categorical domains. Image was created using a licensed version of BioRender.

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Figure 2.

Figure 2.Results of the systematic literature search, indicating the number of papers retained for inclusion at each step. n1 = search 1, n2 = search 2. Following the initial search, publications were excluded that were 1) duplicates across the searches (i.e., detected in PubMed and Web of Science), 2) case studies or reviews, 3) duplicates across domain topics, and 4) did not statistically evaluate potential male/female differences or interactions. *For the Heart Disease and Hypertension domain, 1 additional publication was excluded (15), as it appeared to have the same data set as another publication in the domain. The final count for this domain was ultimately 4. Image was created using a licensed version of BioRender.

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Table 1. Summary of articles identifying sex differences in four domains related to cardiovascular disease and dysregulation in individuals with DS

Sample Size and ReferenceSummary of Major Findings
Congenital heart disease
 1,469 infants with DS (35)Female infants with DS are at higher risk of complete AVSD, any complete, partial, or unspecified AVSD, and ASDII.
 230 infants with DS (8)Risk for CHD, ASD, and severe CHD is higher in female infants.
 116 infants with DS and CHD (18)Higher incidence of CHD in female patients and PDA, and AVSD more common. Poorer survival in female patients.
 487 fetuses with DS (16)Higher incidence of AVSD in female fetuses.
 107 infants & children with DS (20)Higher incidence of any CHD in male patients.
 1,310 infants with DS (10)Higher incidence of CHD and CHD with PDA in in female patients. No sex differences for infants born after 2000. More female patients underwent surgery for CHD repair.
 350 infants with DS (17)Higher incidence of all cardiac lesions in female patients. Incidence of VSD was more common in male patients.
Baseline physiology and risk factors
 106 children with DS (25)Sex is not a predictor of obstructive sleep apnea.
 77 children with DS (21)Weight gain increases the risk of severe obstructive sleep apnea; sex is not a confounding variable.
 111 children with DS (22)Frequency of sleep-disordered breathing is higher in boys and girls had fewer obstructive events.
 15 teenagers with DS (30)Overweight female teenagers had higher levels of insulin resistance.
 81 adults with DS (26)Age, female sex, and level of disability are associated with lower 6-min walk test.
 52 adults with DS (29)No difference in physical activity levels between men and women. Most do not meet current physical activity guidelines.
 1,450 adults with ID, 337 with DS (50)Female sex and DS associated with increased risk of obesity and morbid obesity.
 412 patients with DS (24)Higher rate of obesity, particularly in DS and female children.
 16 individuals with DS (28)Higher body fat percentage and shorter height in male DS participants.
 1,119 individuals with ID (19)Higher rate of mortality in underweight men and in obese women > 25 yr old. Men more likely to be underweight and women more likely to be obese. Hypertension associated with obesity risk.
 52 individuals with DS and 52 controls (13)Sex is not a predictor for blood pressure in DS.
Heart disease and hypertension
 6,493 children receiving anthracycline chemotherapy, 1% with DS (23)Risk of cardiotoxicity in DS is higher and risk for female patients is higher. Total risk correlates with a number of risk factors.
 52 individuals with DS & 52 controls (13)Intramedial thickness (IMT) is lower in DS, and male is a significant predictor of IMT in DS.
 4,081 patients with DS (14)Relative risk of any coronary event is lower in men with DS but not in women.
 1,549 patients with DS and CHD (31)No sex difference in long-term survival in patients with DS and congenital heart disease.
Cerebrovascular disease
 16 with DS (33)Higher incidence of Moyamoya syndrome in girls/women with DS.
 4,081 DS patients (14)Risk of cerebrovascular event in DS is higher and higher in women ≤50 yr old.

ASDII, secundum atrial septal defect; AVSD, atrioventricular septal defect; CHD, congenital heart disease; DS, Down syndrome; ID, intellectual disability; 6MWD, 60-min walk test; PDA, patent ductus arteriosus; VSD, ventricular septal defect.

Retrospective Medical Records Review

A retrospective review of the medical records participating health care organizations was performed using the TriNetX platform. This platform allows investigators to explore aggregate, deidentified patient data from an electronic medical record database. At the time of data analysis, 75 academic medical centers and community hospitals in 29 states provided data to the TriNetX platform, with 107,351,447 patient records contributed. Available data include ICD-10 diagnosis codes, demographics, medications and procedures, and laboratory results, beginning at the time of electronic medical record implementation for each site. Because individually identifying patient information is not accessible, the use of this platform has been determined to be exempt from review by the University of Iowa Institutional Review Board. Medical diagnoses were compared for all patients within the data set. For laboratory results and cardiovascular risk factors, only data from the most recent 10,000 patients within each group are reported by TriNetX.

Patients with a DS diagnosis were identified by ICD-10 codes (Q90). Based on previous reports of median survival of ∼60 yr in DS (1, 2, 32), the general patient population was restricted to patients <60 yr old. Patient counts for congenital heart disease and cardiovascular diseases were obtained using ICD-10 codes and relative risk was computed comparing the DS and general patient counts and men and women within each population (Minitab, State College, PA). Significance was set a priori as P < 0.05. Risk factors for cardiovascular disease were identified and included in the analysis if results were available for at least 200 patients in each population. Risk factors were compared using a Student’s t test (Minitab, State College, PA) with a Bonferroni correction for multiple comparisons where appropriate.

RESULTS

Scoping Literature Review

A summary of the major findings from the papers identified in the scoping review is presented in Table 1.

Domain 1: congenital heart disease.

Consistent across multiple publications, girls with DS have a higher rate of congenital heart disease and, in particular, a higher rate of septal defects (8, 10, 16–18, 35). Although more female patients underwent surgery for congenital heart disease repair (10), mortality was higher in female patients (18). Two papers identified a higher rate of congenital heart disease and ventricular septal defect in male infants (17, 20) and a third reported that sex differences are not apparent in infants with DS born after 2000 (10). Sex differences in congenital heart disease in DS appears to be an emerging area of research with more publications focused on this specific question than questions related to the other domains.

Domain 2: baseline physiology and risk factors.

The majority of papers report an increased risk of obesity in female children and women with DS (19, 24, 30), and this may be associated with increased insulin resistance (30) and increased mortality (19). A single paper, with a smaller cohort, reports increased body fat percentage in men with DS (28). There may be sex-based limitations in the ability to gauge cardiovascular risk using traditional assessment methods (13). There are not sex differences in physical activity between men and women with DS and both sexes fail to meet the daily physical activity guidelines (29). Performance in a 6-min walk test was poorer in women with DS (26). Although neither sex currently meets the physical activity guidelines, it is unclear whether there are sex differences in the incidence of sleep apnea, a risk factor for cardiovascular disease in the general population. Two investigations report no sex difference in sleep apnea incidence (21, 25), the incidence of sleep apnea is higher in boys with DS and girls have fewer obstructive events (22).

Domain 3: heart disease and hypertension.

Carotid artery intramedial thickness is lower in DS. However, in the referenced study, male sex was a predictor of IMT (13) and the risk of a coronary event is lower in men with DS, but not women (14). Girls with DS are at increased risk of heart disease following cardiotoxic chemotherapy (15, 23). There are no reported sex differences in long-term survival in individuals with congenital heart disease (31).

Domain 4: cerebrovascular disease and stroke.

Women and girls with DS are at an increased risk of early cerebrovascular events (14) and Moyamoya syndrome (33). Although there is a higher risk for girls to develop Moyamoya, we uncovered only two studies on the topic using our search terms.

Retrospective Medical Record Review

A cohort of patients without DS (<60 yr old, n = 60,846,311 and 76,989 patients with DS) were identified in the medical records (Table 2). Forty-six percent of the general population was male, compared with 42% of patients with DS, and the DS population was 8 yr younger than the general patient population. Fifty percent of patients with DS had a medical record duration ≥5 yr, compared with 23% of the general population. Both populations had the largest percentage of patients from the southern region of the United States and the fewest patients from the western region (Supplemental Fig. S1).

Table 2. Incidence of cardiovascular disease in age-matched patients with DS and the general patient population in 75 participating health care organizations on or before June 01, 2022

General Population, n
Down Syndrome, n
Overall
General Population
Down Syndrome
Age, yr
Age, yr
Odds ratio
M/F odds ratioM/F odds ratio
ICD10 CodesSex, % MaleRaceSex, % MaleRaceDS/gen pop
Total population60,846,31152% White76,98963% White
33 ± 1630% Unknown25 ± 1622% Unknown
46%14% Black42%13% Black
3% Asian2% Asian
11% Hispanic17% Hispanic
Congenital heart diseaseQ20–Q28736,54426,46342.741.081.37
24 ± 1817 ± 13[42.11–43.39][1.08–1.09][1.32–1.41]
HypotensionI95576,6044,3416.250.811.04
42 ± 1432 ± 18[6.06–6.44][0.81–0.82][0.98–1.11]
HypertensionI10–I165,062,96610,3321.711.240.52
47 ± 1131 ± 16[1.67–1.74][1.24–1.25][0.50–0.54]
POTSI49.8508,1732,4663.930.921.13
39 ± 1526 ± 17[3.77–4.09][0.92–0.93][1.05–1.23]
Ischemic heart diseaseI20–I25998,6943,5042.861.630.8
49 ± 1129 ± 17[2.76–2.96][1.63–1.64][0.75–0.86]
Other heart diseaseI27, I48, I50, I731,132,3549,5727.491.231.15
46 ± 1423 ± 18[7.33–7.65][1.22–1.23][1.1–1.2]
Cerebrovascular diseaseI63, I65–67652,7814,9876.391.000.49
44 ± 1529 ± 15[6.21–6.57][1.00–1.00][0.46–0.52]

Values are means ± SD or odds ratio [95% confidence interval]. DS, Down syndrome; F, female; ICD10, International Classification of Diseases (10th Ed.); M, male; POTS, postural orthostatic tachycardia syndrome. Boldface indicates significant values, P ≤ 0.01.

Overall, the DS population had a significantly higher rate of diagnoses of all cardiovascular diseases evaluated, including other heart disease. Other heart disease includes primary pulmonary hypertension, atrial fibrillation and flutter, heart failure, and peripheral vascular disease. Within the general patient population without DS, men had a higher rate of diagnoses of congenital heart disease, hypertension, ischemic heart disease and other heart disease, whereas women without DS had a higher rate of hypotension and postural orthostatic tachycardia syndrome. In the DS population, men had a higher rate of congenital heart disease, POTS and other heart diseases. The sex differences for hypertension, POTS and ischemic heart disease are reversed for DS compared with the general population (women with DS have higher hypertension and ischemic heart disease risk, however POTS is lower). In addition, women with DS have higher risk of cerebrovascular disease, although no sex differences emerged for the general population with this parameter. There is no difference in risk of developing hypotension between males and females with DS. Age at the time of diagnosis was significantly lower in patients with DS across all disease categories.

Cardiovascular disease risk factors in the most recent 10,000 patients without DS and patients with DS were compared (Table 3). Overall, patients with DS had lower body weight, height, body mass index, systolic and diastolic blood pressure, blood glucose, total cholesterol, high-density lipoprotein, and triglycerides. Only low-density lipoprotein was similar between groups. The standard deviation of the R-R interval, one index of heart rate variability, was also lower in patients with DS. Male patients without DS had higher values for weight, height, standard deviation of the R-R interval, systolic blood pressure, diastolic blood pressure and glucose. Female patients without DS had higher total cholesterol, low-density lipoprotein and high-density lipoprotein compared with males. Sex differences that were similar across groups were height, weight, systolic blood pressure, high-density lipoprotein, and triglycerides. For standard deviation of the R-R interval, diastolic blood pressure, glucose, total cholesterol and low-density lipoprotein, no sex differences were present for DS.

Table 3. Comparison of common cardiovascular risk factors in patients with DS and the general patient population

Down Syndrome (n)
P Values
TotalMaleFemaleTotalMaleFemaleGeneral population vs. Down syndromeGeneral population male vs. femaleDown syndrome male vs. female
Sex, %48525347
Weight, lb194 ± 60.1216 ± 57.4186 ± 56.3163 ± 47.5167 ± 47.4157 ± 47.3<0.001<0.001<0.001
(8,690)(4,169)(4,521)(2,639)(1,458)(1,288)
Height, in.67.2 ± 4.0970.1 ± 3.1464.5 ± 2.861.1 ± 3.2262.9 ± 2.4159.1 ± 2.8<0.001<0.001<0.001
(8,615)(4,129)(4,486)(2,073)(1,134)(1,027)
BMI, kg/m229.2 ± 8.1829 ± 7.7629.4 ± 8.5424.5 ± 8.5823.9 ± 8.0425.2 ± 9.14<0.0010.016<0.001
(9,648)(4,628)(5,020)(5,332)(2,984)(2,541)
SDRR, ms787 ± 190802 ± 200774 ± 180721 ± 205712 ± 224728 ± 190<0.001<0.0010.291
(5,003)(2,307)(2,696)(752)(313)(439)
SBP, mmHg124 ± 19.2125 ± 19.5122 ± 18.7109 ± 15.7109 ± 15.8108 ± 15.5<0.001<0.0010.01
(9,913)(4,746)(5,167)(6,302)(3,533)(3,001)
DBP, mmHg75.3 ± 12.376.5 ± 12.474.3 ± 12.167.3 ± 12.967.6 ± 12.867 ± 12.8<0.001<0.0010.061
(9,887)(4,726)(5,161)(6,209)(3,482)(2,959)
Glucose118 ± 78.1120 ± 61.9115 ± 90.5101 ± 42.8102 ± 46.2100 ± 38.4<0.0010.0030.079
(8,556)(4,105)(4,451)(5,493)(3,023)(2,645)
Total cholesterol176 ± 46.3172 ± 47.3181 ± 44.8170 ± 37.1169 ± 37.7171 ± 36.6<0.001<0.0010.167
(5,860)(2,912)(2,948)(2,566)(1,375)(1,274)
LDL101 ± 3998.4 ± 40.1103 ± 37.7101 ± 30.3101 ± 31.3101 ± 29.51<0.0011
(5,789)(2,869)(2,920)(2,514)(1,355)(1,235)
HDL51.4 ± 19.446.4 ± 1856.2 ± 19.548.1 ± 17.645.6 ± 17.650.9 ± 17.5<0.001<0.001<0.001
(5,795)(2,875)(2,920)(2,564)(1,375)(1,258)
Triglycerides145 ± 119158 ± 128133 ± 108125 ± 94.6132 ± 99.6116 ± 86.3<0.001<0.001<0.001
(5,580)(2,983)(2,997)(2,843)(1,543)(1,388)

Values are means ± SD and reflect patients’ most recent measurements. Down syndrome (DS) population, n = 10,000. For the general patient population (n = 10,000), data for the most recent 10,000 patients are given. BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; SDRR, standard deviation of the R-R interval. Boldface indicates significant values.

DISCUSSION

Sex is increasingly recognized as an important biological variable (34). Given the clear sex differences in overall survival in DS that contrast with the general population, we completed the first comprehensive evaluation of sex differences in cardiovascular disease risk and incidence. Several important differences emerged from our scoping review including an increased risk of cerebrovascular disease and cardiac disease after chemotherapy in females and a lower risk of coronary vascular events in men. Given the paucity of data in the DS literature to comprehensively evaluate cardiovascular risk, we performed a retrospective medical record review to determine whether there are sex differences in cardiovascular risk factors and found several interesting patterns that may explain sex-dependent patterns in cardiovascular disease in DS.

Congenital Heart Disease

The preponderance of the data in the literature supports an increased risk of congenital heart disease in female infants with DS. In particular, female infants are at a higher risk of septal defect, although the mechanism underlying this sex difference is unknown. More than 40% of infants with DS, in general, have a congenital heart defect (35, 36). Others have proposed a “gene dosage amplification” hypothesis to explain this increased risk (37). Chromosome 21 contains several genes that are important in the formation of the extracellular matrix of the myocardium and septum (38). Some of these genes are responsive to estrogen receptors, including RCAN (39), DSCAM1 (40), COL6A1 (41), and COL6A2 (42). The bone morphogenic protein receptor gene ALK2 has also been linked to congenital heart disease risk and is regulated by estrogens (43). Although this possibility has not been investigated, altered expression of extracellular matrix genes by estrogens during the critical period for septal formation could potentially explain the increased incidence of septal defects in female infants. In addition, in other populations, cardiac malformations in females have been observed before gonad development demonstrating a sex chromosome specific role for cardiac defects (44).

Two studies report an increased risk of congenital heart disease or septal defect in male infants and it is worth exploring potential explanations for these differences. Sample sizes of these two studies are 107 and 350 infants and each was sampled from a unique geographic region. It is possible there are environmental factors that contribute to increased risk in these two studies and that these differences are revealed because of geographically restricted sampling within a limited time period. Our larger sample in the medical record review also revealed higher congenital heart disease in males with DS. This finding was surprising based on other reports of infants and fetuses with DS (8). Our cohort includes adults living with these conditions and the data may reflect that male patients with DS are identified later than female patients with DS and were not captured in the publications included in the scoping review. It is also plausible that females are more receptive to surgical interventions for CHD; in these instances, they would be listed as “corrected CHD.” If our medical record cohort only included infants in the immediate perinatal period, we may have observed a different outcome.

It is notable that a single study of 1,310 infants reported that sex differences in congenital heart disease risk are not apparent after 2000 (10). It is possible that improvements in echocardiographic screening has led to the diagnosis of less severe congenital heart defects, although this finding does not fully explain the lack of sex differences after 2000. Overall care of DS infants with CHD may also have improved over the past 20 yr. There is one report observing no sex differences in survival up to 40 yr of age in patients with DS and congenital heart disease (31). However, there remains a critical need to better understand the cardiac physiology of DS, particularly those with CHD versus those never diagnosed with CHD, to appropriately care for individuals with DS across the lifespan. Longitudinal, multiinstitutional studies would be valuable to test hypotheses in this area.

Blood Pressure Regulation

Although lower resting blood pressure is a well-established feature of DS (45), there are minimal reports of sex differences in this important clinical measure. Often in these investigations, data for male and female individuals are combined and presented as an average. Draheim et al. (13) performed a regression analysis for multiple cardiovascular measures and did not find that sex was a predictor of blood pressure. In the first study of blood pressure in DS, male individuals with DS under 40 had similar systolic pressure to the control population, and all other groups had reduced blood pressure (female 20–39 yr and male 40–65 yr) (46), suggesting a potential sex difference for blood pressure in individuals under 40. In our medical record review, we observed a higher incidence of hypertension, hypotension, and POTS in DS, with a higher risk in females for hypertension, lower risk for POTS, and no sex differences for hypotension (Table 2). Women in the general population are at an increased risk of both hypotension and POTS. The medical records also identified lower systolic and diastolic blood pressure, and lower standard deviation of the R-R interval for DS, with sex differences in DS only emerging for systolic blood pressure (Table 3). As an aggregate, the difference in systolic blood pressure between men and women with DS was only 1 mmHg, which it not physiologically meaningful. However, there may be sex-dependent differences in blood pressure that are dependent on age. Future investigations of blood pressure would benefit from presenting male and female data separately, including identifying potential sex differences in various age groups. Hypotension, POTS, and hypertension are all more prevalent in the DS population. The fact that the overall blood pressure is lower in the population of patients with DS (Table 3; Gen Population: 124 ± 19.2 vs. DS: 109 ± 15.7 mmHg) suggests that blood pressure is being managed in patients with hypertension. We did not stratify blood pressure by diagnosis. There are limited data on the use of and compliance with antihypertensives in patients with DS. Future studies of blood pressure as a risk factor, blood pressure variability, and antihypertensive use and compliance, are important given the extending lifespan of this population. In addition, the lower blood pressure in DS suggests that other resting cardiovascular measures may be different for this population, and potentially includes sex differences distinct from the general population. Acknowledging these unique baseline physiological parameters is important for understanding pathophysiology in DS (32). Baseline cardiovascular physiology may be a factor that contributes to the underdiagnoses of comorbidities in DS (47, 48), which is more likely to occur in females with DS (49).

Cardiovascular Risk Factors

Our scoping review reveals limited investigations into cardiovascular risk factors in DS, including obesity, physical activity and sleep apnea. One study observed a higher frequency of sleep-disordered breathing in boys (22), which could influence cardiovascular outcomes. Obesity was more often observed in females with DS (24, 30, 50). The 6-min walk test was also lower in females (26), suggesting reduced fitness in this group. Overall, individuals with DS have an attenuated VO2 peak, which is associated with waist circumference and waist/height ratio, but not other typically associated factors such as lean mass and body fat percentage (27). The medical record review identified that body weight, height, body mass index (BMI), systolic blood pressure, high-density lipoprotein and triglycerides (Table 3) were different between men and women with DS. However, sex differences in other risk factors (diastolic blood pressure, glucose, low-density lipoprotein, and total cholesterol) that are present in the general present are not present in DS. It should be noted that BMI was lower between DS and controls in this cohort. The lower BMI is in contrast to the literature and may be unique to the wider age span in our medical record review. Taken together, these data support that some traditional risk factors for cardiovascular disease may not be appropriate for DS.

Cardiotoxicity Following Chemotherapy

Children with DS have a 10- to 20-fold increased risk of acute lymphoblastic and myeloid leukemias (51, 52). Anthracycline-based chemotherapy is frequently used to treat blood cancers in children and is associated with an increased risk of early onset heart failure (53). Krischer et al. (15, 23) found that both DS and female sex are independently associated with increased risk of anthracycline-induced cardiotoxicity. In addition, Black patients also had an increased risk ratio. Although male and female children with DS were not directly compared, total risk was cumulative so that having more risk factors was associated with an increased probability of developing heart failure. The mechanisms that underlie cardiotoxicity are not entirely understood, nor is the physiological basis for sex differences. Still, girls with DS may benefit from more careful cardiac screening after cardiotoxic chemotherapy.

Heart Disease

Both the scoping and medical record review support that the increased risk of ischemic heart disease for men in the general population is not apparent in DS. In the first study of cardiac disease risk in a large cohort of patients with DS (n = 4,081; age 0–89), adult men with DS were at a reduced risk of coronary events, but not women (14). When separated in three age groups (0–18, 19–50, and 50+), the 51+ age group showed a reduced coronary event risk for men with DS, which was also present when all ages were combined for analysis. Since Sobey 2015 is the first large cohort investigation of coronary events across the lifespan in DS, these data are worth exploring. Women with DS experience early menopause (∼26–40 yr) (54); therefore, it is unlikely that hormone status drove the similar risk for DS women versus controls, which was present at all three age groups. However, early onset menopause is associated with dementia and mortality in DS (55). More investigations are warranted to determine if age of menopause influences cardiovascular events in DS. The male and female DS groups over 50 had a similar number of cardiovascular events (males: 19 ± 10.2 and females: 16 ± 8.7; sample size 186) and may be due to reduced atherosclerosis in DS. DS has classically been viewed as an atheroma free condition, with a reduced risk of heart disease in adulthood. This is not supported by our medical record review (2.86 odds ratio; DS vs. General Population, Table 2).

Few reports have investigated heart disease in older individuals with DS. It should be noted that studies investigating plaques in DS have not considered sex differences, although these studies investigated both sexes (46, 56). Our medical record review identified a higher risk of ischemic heart disease in women with DS versus men. Intramedial thickness, a marker of atherosclerosis, is also lower in DS (13) and males in this study represented a significant predictor of IMT in DS. The reduced and/or absent atherosclerosis in DS may confer protection from some heart disease despite the presence of other cardiovascular risk factors, but more studies are needed to determine the interplay of sex hormones and related cardiovascular risk factors in DS.

Moyamoya

Moyamoya is a cerebrovascular pathology involving arteries in the brain, most often the carotid arteries and branches from the carotid [reviewed recently in Ref. (57)]. The arteries become narrowed and smaller and new, more delicate and frail vessels form. They ultimately may rupture, causing stroke. Moyamoya syndrome is used when a patient has other underlying conditions that may predispose them to Moyamoya (including but not limited to DS) (58) and Moyamoya disease is used when other risk factors are not present. Feghali observed 63% of patients with Moyamoya syndrome were female, whereas 78% of those with Moyamoya disease were female (59). Therefore, girls and women are at a higher risk of Moyamoya even in the absence of other underlying conditions. Jea et al. (33) identified a higher risk of Moyamoya syndrome for females with DS. The age at onset for Moyamoya is also earlier in DS (60). Kainth et al. (60) suggests the increased Moyamoya incidence could be related to vascular abnormalities, differential expression of the α chain of collagen type IV encoded on chromosome 21, and/or increased CHD in DS. Multiple other groups report an apparent increased risk of Moyamoya syndrome in females with DS (58, 59, 61, 62) but Jea et al. are the only group to directly compare male and female individuals with DS in our analysis. These data are consistent with our medical record review, and more research is needed in larger cohorts to determine the mechanisms underlying increased risk in females with DS.

Limitations

This is the first study to evaluate potential sex differences in cardiovascular disease risk factors in a large cohort of individuals with DS, but there are some limitations to our retrospective medical record review. Because data are reported in aggregate, we are not able to case control match and we cannot look for associations of risk factors within single individuals. TriNetX does not allow for population level matching (age, sex, race, etc.) in large populations, like the general patient population reported here. Because participating centers report deidentified data, single individuals cannot be identified. It is possible that an individual may be represented more than once if they obtain care from more than one reporting center. We note that 50% of the patients with DS in the data set have a medical record duration ≥5 yr, compared with 23% of the general population. It is, therefore, less likely that patients with DS are represented multiple times. The regional distribution of the data is also similar, with the largest portion of the population receiving care in the southern region of the United States and the fewest receiving care in the western region (Supplemental Fig. S1).

When comparing laboratory results and risk factor data, TriNetX reports data from a subset of the most recent patients, does not allow for case-controlled matching, and does not report the date the data were obtained to protect patient privacy. It is possible that these data were not obtained within the exact same date range. It is possible, and even likely, that some of the data were collected during the COVID-19 pandemic. Still, this data set contains the largest number of patients with DS available and provides valuable information for future hypothesis generation and sample size determination. The limitations of the TriNetX platform highlight the importance of a regionally diverse DS-specific database, with an appropriate control group, that would allow for future exploration of cardiovascular risk in this population.

Although we acknowledge the limitations of not being able to match the populations more closely, this is one of the first data sets to include middle-aged and aging individuals with DS. We hope that future groups will endeavor to explore differences within more narrow age windows.

We restricted the general patient population based on the median survival age in DS, but the general patient population was 8 yr older. We may actually underestimate the relative risk in DS. We demonstrate the age of onset for all cardiac disease is younger in DS and that the sex differences observed in the general population for hypotension, hypertension, POTS, ischemic heart disease, and cerebrovascular are lost or reversed in DS. There are additional factors that may influence earlier onset cardiovascular risk that we did not capture here. We are not able to quantify physical activity patterns. Congenital heart disease is more prevalent in DS, and babies with DS are more likely to be born prematurely and smaller for gestational age, which independently increases the risk of early onset cardiovascular disease (63). Individuals with DS are more likely to have received cardiotoxic chemotherapy because of their increased risk of pediatric leukemia (64) and women with DS enter menopause earlier than the general population (54).

Our medical record review is limited to institutions in the United States. Cardiovascular risk factor data (Table 3) was not available for every patient. To address this issue, we only included variables for which at least 200 patients with DS had data and the most recent 10,000 patients in the general patient population. Despite the limitations, these data are valuable for sample size calculations needed for prospective studies and provide important rationale for future case-controlled investigations.

The scoping review used the search terms “male” and “female.” It is possible that items were missed in the literature that did not contain these terms but did study sex differences. For example, “girl/boy” or “gender” or “sex differences” may have been used in other instances. We chose to focus the scoping review using male/female as these terms are most universal. By including studies that provided male/female data along with statistical measures related to potential sex differences, a large body of the DS literature is not presented in our findings. We hope this point provides rationale for future studies to include separate data for males and females. At the same time, we want to recognize that many references were not included that investigated cardiovascular physiology in DS.

Conclusions

This investigation compared sex differences in the DS population with respect to cardiovascular disease and dysregulation. Based on the results of our scoping review, we conclude female individuals with DS are at higher risk of cardiotoxicity from chemotherapy, coronary disease, and Moyamoya syndrome, relative to the general population. The scoping review was mixed for increased female risk for CHD, whereas the retrospective medical record review detected a higher risk for males with DS across the ages we studied. When comparing DS and controls in the medical records review, there is increased incidence for all cardiac diseases and all risk factors except low-density lipoprotein for DS. However, sex differences are not present in DS for the standard deviation of the R-R interval, diastolic blood pressure, glucose, total cholesterol or low-density lipoprotein levels. The data reported here support that cardiovascular disease has higher incidence in DS, and traditional risk factors are not universally predictive of cardiovascular disease risk in the DS population and this important point should be considered in the care of this population.

DATA AVAILABILITY

Data will be made available upon reasonable request.

SUPPLEMENTAL DATA

Supplemental Fig. S1: https://doi.org/10.6084/m9.figshare.22068902.v1.

Supplemental Table S1: https://doi.org/10.6084/m9.figshare.22070120.v1.

GRANTS

This work was supported by National Institute of Child Health and Human Development Grants 1R21HD099573 and 3R21HD099573 (to L. R. DeRuisseau), American Physiological Society Hearst fellowship grant (to L. D. M. Flores), and American Cancer Society research scholar grant (to M. L. Bates). TriNetX is supported by the Institute for Clinical and Translational Science at the University of Iowa. The Institute for Clinical and Translational Science at the University of Iowa is supported by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) Program Grant UL1TR002537. CTSA program is led by the NIH’s National Center for Advancing Translational Sciences.

DISCLAIMERS

This publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.L.B. and L.R.D. conceived and designed research; M.L.B., A.V., L.D.M.F., Y.P., and L.R.D. performed experiments; M.L.B., A.V., L.D.M.F., Y.P., M.B., Y.P., and L.R.D. analyzed data; M.L.B., A.V., L.D.M.F., M.B., and L.R.D. interpreted results of experiments; M.L.B., A.V., L.D.M.F., Y.P., and L.R.D. prepared figures; M.L.B. and L.R.D. drafted manuscript; M.L.B., A.V., M.H.T., and L.R.D. edited and revised manuscript; M.L.B., A.V., L.D.M.F., Y.P., M.B., M.H.T., and L.R.D. approved final version of manuscript.

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