Single-Beat Method Echocardiographic Comparison of Ventricular Arterial Coupling in Adults with and without Down syndrome

Abstract

Adults with Down syndrome (Ds) demonstrate unique cardiovascular features, including smaller left ventricular volumes and lower blood pressure. Ventricular-arterial coupling (VAC), a key measure of cardiovascular efficiency, has not been previously studied in this adult population. Understanding VAC in adults with Ds may reveal compensatory mechanisms that maintain cardiac output despite distinct cardiovascular characteristics. This study used echocardiographic parameters to compare the VAC ratio of adults with and without Ds.

Baseline echocardiographic data were collected from 28 adults with Ds and 18 adults without Ds (aged 18 – 35 years), all of whom had low physical activity levels. The VAC ratio was calculated using the single-beat method.

Adults with Ds had lower VAC ratios and diastolic blood pressure, faster pre-ejection times, shorter normalized systolic durations, and a higher ejection fraction than adults without Ds.

Adults with Ds exhibit distinct cardiovascular adaptations, including a lower VAC ratio and a shorter systolic duration, suggesting increased cardiac workload. Higher ejection fraction and faster pre-ejection period indicate potential compensatory mechanisms to maintain cardiac output, while lower diastolic blood pressure may reduce coronary perfusion and preload. These findings demonstrate differences in cardiac function and timing in adults with Ds in this study.

NEW AND NOTEWORTHY

This study reveals, for the first time, that adults with Down syndrome exhibit significantly lower ventricular-arterial coupling ratios, reflecting distinct cardiac timing and functional adaptations. These findings could indicate a compensatory mechanism to maintain cardiac output despite reduced diastolic pressure and smaller cardiac chambers, providing novel insight into the integrated cardiovascular physiology of adults with Down syndrome and its potential implications for exercise tolerance and long-term cardiovascular health.

INTRODUCTION

Down syndrome (Ds) is a chromosomal disorder associated with a range of cardiovascular abnormalities (1, 2). The average life expectancy for individuals with Ds has increased from approximately 24 years in the 1980s to 60 years by 2020 (3). While congenital heart defects in individuals with Ds have been extensively studied, less attention has been given to cardiac function in adults with Ds, specifically ventricular arterial coupling (VAC).

Ventricular-arterial coupling (VAC) describes the dynamic interaction between cardiac performance and the arterial system (4). VAC can be quantified as the ratio of arterial elastance (Ea) to end-systolic elastance (Ees) of the left ventricle (4). Arterial elastance (Ea) represents the afterload (the pressure the heart must overcome to eject blood) and is influenced by systemic vascular resistance, arterial compliance, stroke volume, heart rate, and blood pressure (5, 6). End-systolic elastance reflects the intrinsic contractile strength of the left ventricle. It is a mostly load-independent measure of myocardial function, minimally affected by preload (ventricular filling) and afterload (arterial resistance) (4). Ees is the ratio of end-systolic pressure to end-systolic volume, representing the slope of the end-systolic pressure-volume relationship (7). This parameter is influenced by left ventricular geometry and wall stiffness (8).

The gold standard for measuring Ees is invasive intraventricular catheterization (9); however, a widely used non-invasive single-beat method has been developed (10, 11). Ventricular-arterial coupling ratios typically range from 0.5 to 1.0, with values closer to 1.0 representing optimal energy transfer between the heart and the arterial system (12, 13). Values above 1.0 may indicate a ventricular-arterial mismatch, as seen with increased arterial stiffness or impaired contractility, which is commonly associated with aging or hypertension (14). Lower VAC values (<1.0) are often considered more efficient, reflecting favorable coupling (14). However, a lower VAC may reflect a compensatory increase in ventricular work, where the heart generates greater contractile effort to maintain stroke volume despite lower preload and smaller chamber size. In this scenario, the reduced VAC may not purely reflect enhanced efficiency, but rather an adaptive response to underlying structural or hemodynamic constraints.

Individuals with Ds exhibit higher rates of obesity (2), premature aging (15), reduced physical activity (16), endothelial cell dysfunction (17), diabetes (18), and altered cardiac autonomic control (19, 20). In adults with Ds, exercise intolerance is thought to be partially related to autonomic dysfunction, which can impair heart rate and blood pressure regulation (19). Despite these contributing factors, they consistently demonstrate lower blood pressure (21), particularly diastolic blood pressure, than individuals without Ds (22, 23). Also, adults with Ds typically do not exhibit age-related increases in hypertension or arterial stiffness (24). Chronic hypotension in individuals with Ds may reduce arterial distending pressure, potentially contributing to preserving arterial function (25).

Adults with Ds have significantly lower left ventricular mass indexed to body surface area and smaller left ventricular volumes than adults without Ds (64 ± 17 vs. 94 ± 17 g/m²; p < 0.001) (22). In addition, individuals with Ds exhibit a markedly reduced cardiac output indexed to body surface area following exercise (2.9 vs. 3.7 l/min/m², p < 0.001) (23). Smaller heart sizes may contribute to reduced exercise tolerance due to limited cardiac reserve (26). In studies of adult females without Ds, smaller hearts, characterized by lower left ventricular mass, are associated with higher ejection fraction and fractional shortening, serving as compensatory mechanisms to maintain adequate cardiac output relative to adult males (27). It is unknown if a similar mechanism exists in individuals with Ds.

Ejection fraction, a key echocardiographic measure of left ventricular systolic function, represents the heart’s pumping efficiency (28). Previous studies involving children and adults with Ds have consistently reported higher ejection fractions than those without Ds (22, 29). In addition, several studies have documented diastolic dysfunction in adults with Ds relative to controls (30, 31).

Ventricular-arterial coupling (VAC) reflects the integrated interaction between left ventricular function and arterial load. Examining both components of the VAC ratio, arterial elastance (Ea) and the end-systolic elastance (Ees), may provide deeper insight into the unique cardiovascular dynamics observed in adults with Down syndrome. Given previously reported differences in vascular health and structural and functional cardiac alterations in this population, several parameters contributing to the calculation of Ea and Ees are likely to be affected, ultimately influencing the VAC ratio. Assessing the VAC ratio may also offer a more nuanced understanding of potential protective or compensatory mechanisms to preserve cardiac output in this population.

Accordingly, this study used echocardiographic parameters to compare ventricular-arterial coupling in adults with and without Down syndrome.

MATERIALS AND METHODS

Design and Study Population

This study is a subset of a larger randomized controlled trial investigating blood flow regulation and exercise in individuals with Down syndrome (Ds) (NCT04854122). The present analysis used baseline echocardiography data from male and female participants with and without Ds. Eligible participants were adults aged 18–35 with a low-active lifestyle, defined as engaging in less than 30 minutes of moderate-intensity physical activity daily. Individuals with Ds were required to have a confirmed diagnosis of trisomy 21 and stable thyroid function for at least six months. Exclusion criteria included unrepaired congenital heart defects, vascular or atherosclerotic disease, asthma or pulmonary disease, high blood pressure (>140/90 mmHg), very low blood pressure (<90/60 mmHg), a history of pre-syncope or syncope, diabetes (HbA1c > 7.5% or diabetes medication use), use of medications that could affect blood pressure, heart rate, or arterial function, anti-inflammatory drugs or NSAIDs, smoking, and pregnancy. Participants were recruited from the University of Nevada, Las Vegas campus through Down syndrome support groups, word of mouth, flyers, and social media. Data collection and analysis were conducted at the University of Nevada, Las Vegas Cardiovascular Research and Exercise Laboratory between August 2021 and May 2024. This study was reviewed and approved by the Institutional Review Board of the University of Nevada, Las Vegas (IRB # 1442844-EXP). Written informed consent was obtained from all participants and their legally authorized representatives.

Anthropometric Baseline Measures

Height (cm) and weight (kg) were recorded using Health-o-meter professional 500KL. Body mass index was calculated as weight (kg) divided by height squared (m²), and body surface area (m²) was determined using the DuBois formula (32). Systolic and diastolic blood pressure (SBP and DBP) and heart rate were measured using a commercially available Mobil-O-Graph blood pressure monitor following ten minutes of supine rest in a quiet, dimly lit room. Mean arterial pressure (MAP) was calculated as 1/3*SBP+2/3*DBP. Total peripheral resistance (TPR) was calculated by dividing mean arterial pressure (MAP) by cardiac output, as measured using Doppler echocardiography in the apical four-chamber view (see below). Augmentation index and pulse wave velocity from the Mobil-O-Graph were used as descriptive measures of arterial function (33).

Echocardiography

A comprehensive baseline echocardiographic examination was conducted for all participants in this study by a certified Registered Diagnostic Cardiac Sonographer, with individuals positioned in either the supine or lateral decubitus position. Examinations were performed using a commercially available ultrasound system (Aloka-Hitachi Arietta 70/CV). Standard parasternal long-axis (PLAX) and apical four- and five-chamber (A4 and A5) views were obtained.

Left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume were measured in the A4 view using Simpson’s biplane method by tracing the endocardial borders at end-diastole and end-systole. Stroke volume (SV) was calculated as LVEDV minus LVESV, and the ejection fraction (EF) was calculated as (LVEDV − LVESV)/LVEDV.

Pre-ejection time (PEP) was obtained using M-mode in PLAX view at the level of the aortic valve. PEP was defined as the interval from the onset of the QRS complex on the ECG to the opening of the aortic valve, as indicated by the onset of the aortic cusp separation on M-mode. Left ventricular ejection time (LVET) was measured using pulsed-wave Doppler from the apical (A5) view, defined as the duration between the onset and cessation of forward flow across the aortic valve. All measurements followed guidelines from the American Society of Echocardiography (28).

Calculations Measurements VAC

The ventricular-arterial coupling (VAC) ratio, a measure of the cardiovascular system efficiency, was calculated non-invasively using the single-beat method developed by Chen et al. (10) and further refined by Holm et al. (11). It is expressed as:

$$\mathrm{V}\mathrm{A}\mathrm{C}=\mathrm{E}\mathrm{a}/\mathrm{E}\mathrm{e}\mathrm{s}$$

Arterial elastance quantifies the effective arterial load by the left ventricle during systolic ejection. It is calculated by the following formula:

$$\mathrm{E}\mathrm{a}=(\mathrm{S}\mathrm{B}\mathrm{P}\times 0.9)/\mathrm{S}\mathrm{V}$$ (Formula 1)

Where: SBP: Systolic blood pressure measured via an arm cuff.

SV: Stroke volume derived from Doppler echocardiography.

End-systolic elastance (Ees), an index of left ventricular contractility, was estimated using the single-beat method (11).

The first step was to calculate the systolic period.

$$\begin{gathered} \mathrm{S}\mathrm{y}\mathrm{s}\mathrm{t}\mathrm{o}\mathrm{l}\mathrm{i}\mathrm{c}\mathrm{p}\mathrm{e}\mathrm{r}\mathrm{i}\mathrm{o}\mathrm{d}=\mathrm{P}\mathrm{E}\mathrm{P}+\mathrm{L}\mathrm{V}\mathrm{E}\mathrm{T}(\mathrm{p}\mathrm{r}\mathrm{e}-\mathrm{e}\mathrm{j}\mathrm{e}\mathrm{c}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{i}\mathrm{m}\mathrm{e}(\mathrm{P}\mathrm{E}\mathrm{P})+\mathrm{l}\mathrm{e}\mathrm{f}\mathrm{t}\mathrm{v}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{i}\mathrm{c}\mathrm{u}\mathrm{l}\mathrm{a}\mathrm{r} \\ \mathrm{e}\mathrm{j}\mathrm{e}\mathrm{c}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{i}\mathrm{m}\mathrm{e}(\mathrm{L}\mathrm{V}\mathrm{E}\mathrm{T}\left)\right). \end{gathered}$$ (Formula 2a)

Then, the systolic period was used to calculate the Normalized Systolic Duration (tNd) using the formula:

$$\mathrm{t}\mathrm{N}\mathrm{d}=\mathrm{P}\mathrm{E}\mathrm{P}/\mathrm{s}\mathrm{y}\mathrm{s}\mathrm{t}\mathrm{o}\mathrm{l}\mathrm{i}\mathrm{c}\mathrm{p}\mathrm{e}\mathrm{r}\mathrm{i}\mathrm{o}\mathrm{d}.$$ (Formula 2b)

Using the calculated Normalized Systolic Duration, the next step was to calculate the Averaged Normalized Elastance End(Avg) using a seventh-order polynomial:

$$\begin{gathered} \text{End(Avg)}=0.35695-7.2266\mathrm{t}\mathrm{N}\mathrm{d}+74.249{\mathrm{t}\mathrm{N}\mathrm{d}}^2-307.39{\mathrm{t}\mathrm{N}\mathrm{d}}^3+684.54{\mathrm{t}\mathrm{N}\mathrm{d}}^4- \\ 856.92{\mathrm{t}\mathrm{N}\mathrm{d}}^5+571.95\mathrm{t}\mathrm{N}{\mathrm{d}}^6-159.1{\mathrm{t}\mathrm{N}\mathrm{d}}^7 \end{gathered}$$ (Formula 3)

The Estimated Normalized Elastance End(Est) was then calculated using the formula:

$$\mathrm{E}\mathrm{n}\mathrm{d}\left(\mathrm{E}\mathrm{s}\mathrm{t}\right)=0.0275-0.165\mathrm{E}\mathrm{F}+0.3656(\mathrm{D}\mathrm{B}\mathrm{P}/[\mathrm{S}\mathrm{B}\mathrm{P}\times 0.9\left]\right)+0.515\mathrm{E}\mathrm{n}\mathrm{d}\left(\mathrm{A}\mathrm{v}\mathrm{g}\right)$$ (Formula 4)

Where: EF: Ejection fraction derived from echocardiographic measurements and

DBP: Diastolic blood pressure measured via arm cuff.

End-systolic Elastance (Ees) is then determined using the formula:

$$\mathrm{E}\mathrm{e}\mathrm{s}=(\mathrm{D}\mathrm{B}\mathrm{P}-[\mathrm{E}\mathrm{n}\mathrm{d}\left(\mathrm{E}\mathrm{s}\mathrm{t}\right)\times \mathrm{S}\mathrm{B}\mathrm{P}\times 0.9\left]\right)/(\mathrm{S}\mathrm{V}\times \mathrm{E}\mathrm{n}\mathrm{d}(\mathrm{E}\mathrm{s}\mathrm{t}\left)\right).$$ (Formula 5)

Finally, the VAC ratio, a dimensionless index of the cardiovascular system efficiency, was calculated.

$$\mathrm{V}\mathrm{A}\mathrm{C}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}=\mathrm{E}\mathrm{a}/\mathrm{E}\mathrm{e}\mathrm{s}$$ (Formula 6)

Statistical Analysis

Data were evaluated for skewness and kurtosis, and normality was tested using the Shapiro-Wilk test. Study group characteristics were reported as mean and standard deviation for continuous variables. Baseline sex distribution differences were analyzed with chi-square tests. Descriptive characteristics and outcome measures were compared between individuals with and without Down syndrome using independent t-tests for normally distributed data or the Mann-Whitney test for non-normally distributed outcomes. Cohen’s d effect sizes were calculated for parametric comparisons and classified as small (d = 0.2), medium (d = 0.5), and large (d = ≥ 0.8) (34). All analyses were conducted with IBM SPSS Statistics (Version 29.0.2.0, SPSS Inc., Chicago, IL, USA).

Results

Descriptive Characteristics

Our study included 28 adults with Down syndrome (n=28) and 18 adults without Down syndrome (n=18). Table 1 summarizes their descriptive characteristics. In addition, a history of congenital heart defects was present in n=13 adults with Down syndrome, of which n=7 had a surgical repair in the first months (ASD only n=1, ASD/VSD n=2, ASD/AVSD n=1, PDA n=2, undefined hole(s) n=1) and for n=6 it closed spontaneously (ASD only n=1, ASD/VSD n=1, ASD/PDA n=1, undefined hole(s) n=3). Compared to adults without Down syndrome, those with Down syndrome were shorter in stature, had a higher body mass index, a lower diastolic blood pressure, and a lower mean arterial pressure.

Table 1.

Descriptive Characteristics

Characteristic	Individuals with Ds (n=28)	Individuals without Ds(n=18)	p-value	Effect Size (Cohen’s d)
Male	13 (46%)	4 (22%)	0.085a
Age (yrs)	25.2 ± 4.7	23.2 ± 3.5	0.118	−0.485
Height (cm)	150.3 ± 7.6	163.3 ± 10.6	<0.001*	1.467
Weight (kg)	72.0 ± 18.3	68.4 ± 16.3	0.503	−0.205
BMI (kg/m2)	31.9 ± 7.9	25.6 ± 5.2	0.005*	−0.907
BSA (m2)	1.66 ± 0.21	1.73 ± 0.23	0.302	0.318
SBP (mmHg)	116.1 ± 11.3	118.0 ± 11.1	0.583	0.168
DBP (mmHg)	69.8 ± 5.9	75.2 ± 8.3	0.015*	0.768
HR (bpm)	62.0 ± 8.7	62.9 ± 11.3	0.745	0.100
MAP (mmHg)	85.2 ± 6.5	90.3 ± 8.7	0.038*	0.677
CO (L/min)	2.12 ± 0.62	2.38 ± 0.94	0.283	0.343
TPR (mmHg × min/L)	44.31 ± 16.05	44.48 ± 19.99	0.714b
Augmentation Index (%)	17.6 ± 9.9c	21.8 ± 14.0 d	0.291	0.360
Augmentation Index @HR75 (%)	11.2 ± 11.6c	15.1 ± 12.0 d	0.288	0.333
Pulse Wave Velocity	5.1 ± 0.44c	5.0 ± 0.49 d	0.489	0.216

^*Statistically significant (p < 0.05)

^aChi-square

^bMann-Whitney test

^cn=27

^dn=17

Abbreviations: body mass index, BMI; body surface area, BSA; systolic blood pressure, SBP; diastolic blood pressure, DBP; heart rate, HR; mean arterial pressure, MAP; total peripheral resistance, TPR.

VAC Outcome Measures

Table 2 presents the results of Ventricular-Arterial coupling (VAC). In our study, adults with Down syndrome had a faster Pre-Ejection time (PEP), a shorter normalized systolic duration (tNd), lower End(Avg), End(Est), and ventricular-arterial coupling (VAC) with a higher left ventricular ejection fraction (LVEF) than adults without Down syndrome.

Table 2.

VAC Outcome Measures

Formula #	Parameter	Ds		Non-Ds		T-Test
		N	Mean (SD)	N	Mean (SD)	p-value	Cohen’s D Effect size
1	SBP (mmHg)	28	116.1 ± 11.1	18	118.0 ± 11.1	0.582	0.168
	Stroke Volume (mL)	28	34.7 ± 10.2	18	38.5 ± 14.8	0.309	0.311
	Ea (mmHg/mL/m2)	28	3.27 ± 1.06	18	3.19 ± 1.30	0.620b	N/A
2	Pre-Ejection time (PEP) (ms)	28	100.43 ± 13.40	18	115.33 ± 16.76	0.002*	1.01
	Left ventricular Ejection time (LVET) (ms)	28	362.11 ± 40.24	18	363.78 ± 43.53	0.895	0.040
	Systolic period (ms)	28	462.54 ± 40.03	18	479.11 ± 51.55	0.228	0.370
2b	tNd	28	0.2183 ± 0.032	18	0.2412 ± 0.028	0.017*	0.747
3	End(Avg)	28	0.3051 ± 0.048	18	0.3401 ± 0.039	0.013*	0.781
4	LVEF (p.e.0.60)	28	0.6692 ± 0.054	18	0.6052 ± 0.044	<0.001*	−1.270
	DBP (mmHg)	28	69.8 ± 6.0	18	75.2 ± 8.3	0.015*	0.768
	End(Est)	28	0.3196 ± 0.036	18	0.3619 ± 0.027	<0.001*	1.27
5	Ees (mmHg/mL/m2)	28	3.58 ± 1.05	18	3.12 ± 1.45	0.222	−0.374
6	VAC	28	0.919 ± 0.14	18	1.06 ± 0.14	0.002*	0.969

^*Statistically significant (p < 0.05)

^bMann-Whitney test

N/A = not available due to the use of a non-parametric test

Abbreviations: Ds, Down syndrome; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; SV, stroke volume; PEP, pre-ejection time; LVET, left ventricular ejection time; tNd, normalized systolic duration; End(Avg), average end-systolic pressure; Ea, arterial elastance; End(Est), estimated end-systolic pressure; Ees, end-systolic elastance; VAC, ventricular-arterial coupling.

Discussion

To our knowledge, this is the first study to examine the ventricular-arterial coupling interaction in adults with Ds. We found a lower value for ventricular-arterial coupling (VAC) in adults with Ds, compared to adults without Ds. Traditionally, a lower VAC has been interpreted as an indication of improved ventricular-arterial matching. However, given the findings of elevated ejection fraction, altered cardiac timing, smaller cardiac size, and documented exercise intolerance in this population, the lower VAC could also be indicative of compensatory mechanisms rather than enhanced cardiovascular efficiency.

When evaluated independently, neither arterial elastance (Ea) nor end-systolic elastance (Ees) differed significantly between groups. However, the VAC ratio (Ea/Ees) captured subtle yet meaningful differences in ventricular-arterial coupling that were not apparent from Ea or Ees alone. In adults with Ds, both Ea and Ees were slightly higher than in controls, but a higher Ees relative to Ea resulted in a VAC ratio less than 1 (Ea < Ees). Additionally, significant group differences were observed in End(Avg) and End(Est) values, further supporting distinct cardiovascular dynamics in adults with Ds.

A reduction in End(Avg) may reflect decreased end-systolic volume, altered left ventricular geometry (8, 35), or changes in cardiac timing. Vis et al. (22) reported smaller left ventricular mass, end-diastolic, and end-systolic volumes in adults with Ds. In smaller hearts, a greater proportion of the end-diastolic volume is ejected with each contraction, resulting in a reduced end-systolic volume. While this pattern may help maintain ejection fraction at rest, it may come at the cost of reduced cardiac reserve (the heart’s ability to increase output during stress or exercise) (36). The smaller ventricular cavity size observed in adults with Ds (22) likely limits the absolute volume of blood available for ejection, placing greater emphasis on contractile efficiency to preserve stroke volume (37, 38). Although LVET was similar between groups, the shorter pre-ejection period (PEP) observed in adults with Ds may reflect an adaptation in which the ventricle generates pressure more rapidly to maximize ejection time within each cycle. While conventionally considered beneficial, this pattern, when coupled with increased LVEF and smaller ventricular volumes, may represent a compensatory strategy rather than enhanced cardiovascular efficiency, as smaller volumes constrain the amount of blood available for ejection. Additionally, systolic duration shortens when the heart ejects a larger proportion of blood more rapidly and forcefully, which may further impact ventricular-arterial dynamics.

The elevated left ventricular ejection fraction observed in adults (22) and children (29) with Ds may represent a compensatory response rather than an indication of enhanced cardiac efficiency to maintain cardiac output in the face of challenging hemodynamic conditions (38). Under normal physiological conditions, smaller ventricular chambers and reduced preload would be expected to yield normal or decreased ejection fraction; however, adults with Ds demonstrate the paradoxical combination of constrained ventricular filling with supernormal contractile performance. This counter-physiological pattern suggests that the myocardium is operating under chronic compensatory strain, expending greater contractile effort to maintain stroke volume despite structural and hemodynamic limitations. Rather than indicating superior cardiac function, the elevated ejection fraction likely reflects a state of adaptive overwork where the heart has limited contractile reserve. This could help explain the well-documented reduced exercise capacity in this population (39). This interpretation reframes the lower VAC ratio as enhanced systolic performance as a marker of cardiovascular vulnerability rather than efficiency, with implications for long-term cardiac health surveillance in adults with Ds. These findings are consistent with other populations with smaller ventricular cavities, such as those reported by Foulkes et al., in which a higher LVEF may help sustain stroke volume despite reduced ventricular volume (26). In the present study, the combination of increased LVEF, shorter pre-ejection period, and lower ventricular-arterial coupling (VAC) in adults with Ds may suggest compensatory cardiovascular mechanisms aimed at maintaining stroke volume in the face of reduced ventricular volume and systemic pressure. While these features are often interpreted as efficient, we propose that they may instead reflect increased physiological demand at rest, where the heart contracts more forcefully and rapidly to sustain adequate cardiac output. This interpretation highlights the possibility that adaptive strain rather than simple efficiency may help explain the unique cardiovascular profile observed in adults with Ds (26, 38).

The shorter and faster pre-ejection time (PEP) and shorter total normalized systole duration (tNd) observed in adults with Ds suggest a cardiac cycle characterized by quicker and more forceful ventricular contraction, particularly as ejection time (LVET) remained unchanged between groups. While a shorter PEP with preserved LVET is often interpreted as a sign of systolic efficiency, we propose that in the context of smaller ventricular cavities and lower preload, this pattern may also reflect a state of increased myocardial workload to sustain stroke volume at rest. In other words, the heart appears to be working harder and faster within a constrained filling environment, maintaining cardiac output through accelerated timing and elevated ejection fraction.

In this study, adults with Ds exhibited significantly lower diastolic blood pressure than adults without Ds. Diastolic blood pressure plays an essential role in coronary perfusion, as it provides the driving pressure necessary for oxygen-rich blood to flow into the coronary arteries and supply the myocardium (40). When diastolic blood pressure is reduced, coronary perfusion may be compromised, potentially prompting the heart to compensate by increasing its systolic workload, evidenced by the higher left ventricular ejection fraction (LVEF) (41), observed in adults with Ds in this study. A lower diastolic blood pressure may be associated with reduced systemic arterial pressure and venous return, resulting in diminished preload (blood volume returning to the heart) (35). This reduction in preload may contribute to the lower cardiac reserve previously reported in individuals with Ds (23).

In the current study, a trend towards higher end-systolic elastance (Ees) in adults with Ds was observed compared to controls; the difference did not reach statistical significance, however, it is a likely contributor to the lower observed VAC ratio, given that Ees is the denominator in the mathematical calculation (Ea/Ees) (14). End-systolic elastance is used as a robust index of left ventricular contractility and is considered a direct measure of intrinsic myocardial contractility, as it is independent of loading conditions (42).

Overall, this study identified distinct cardiovascular characteristics in adults with Down syndrome, most notably altered ventricular-arterial coupling (VAC). The lower VAC ratio (<1.0) observed in adults with Ds was likely driven by the trend towards a greater proportional increase in ventricular contractility (Ees) relative to arterial load (Ea), even though neither change was statistically significant on its own. A lower ventricular-arterial coupling ratio does not necessarily indicate a reduced arterial load; instead, it may reflect a compensatory state in which increased myocardial contractility preserves the heart’s efficiency in interacting with the arteries, despite challenging underlying hemodynamic conditions. These differences indicate potential inefficiencies in cardiovascular function, with the heart likely expending more energy to maintain cardiac output.

The shorter pre-ejection time (PEP), decreased estimated normalized elastance (End(Est)), and reduced normalized systolic duration (tNd) observed in this study support the interpretation of mechanical adaptations in cardiac function. These findings suggest specific timing and contractile adjustments. Additionally, previous reports of smaller end-systolic volumes in this population imply that the heart spends less time in systole, further supporting the presence of compensatory mechanisms to preserve cardiac output at rest.

Despite a lack of significant group differences in total peripheral resistance (TPR) between groups (p = 0.714), adults with Ds had lower diastolic blood pressure, which likely contributed to a reduction in afterload. This may have influenced arterial elastance (Ea), which was comparable between groups, and complicates the interpretation of ventricular arterial coupling (VAC). The augmentation index and pulse wave velocity were not significantly different between the groups, with small effect sizes only for the augmentation index. The lower VAC observed in adults with Ds may therefore reflect combined effects of both subtle vascular differences, such as lower diastolic blood pressure, and cardiac adaptations. As peripheral resistance was similar between groups, the better VAC likely results from how the heart adapts to optimize its performance, independent of changes in the vascular system.

This study had several strengths. To our knowledge, it is the first to compare ventricular-arterial coupling between adults with and without Down syndrome. While this study enabled the identification of group differences and associations, its cross-sectional design limits the ability to infer causality. The study included well-matched control participants, used comprehensive echocardiographic analysis using guideline-recommended methods, and incorporated both functional (e.g., LVEF, PEP, LVET) and hemodynamic (e.g., Ea, Ees, VAC) parameters to provide a multidimensional assessment of cardiovascular function. Following recent consensus on the assessment of VAC (33), arterial function measures were included for additional context, however, the consensus statement also recommended to include myocardial function markers such as global longitudinal strain. Unfortunately, the required speckle tracking modality for this measure was not used for data collection, which was one of the limitations of this study.

The sample size was adequate for detecting broad group-level differences; however, it may have been insufficient to explore more subtle patterns or subgroup effects. Additionally, the sample size included a higher proportion of females overall (54% in the Ds group and 78% in the control group), and we did not stratify the analysis by sex. Given the novelty of this research in this population, the potential influence of sex on cardiovascular measures remains unclear. Future studies should consider sex-based stratification to address this limitation.

To confirm and expand upon these findings, more extensive and diverse samples, as well as longitudinal study designs, are needed to better understand the trajectory and clinical relevance of ventricular-arterial coupling in adults with Down syndrome across the lifespan.

Conclusion

This study identified significant differences in ventricular-arterial coupling (VAC) between adults with Down syndrome and those without Down syndrome, highlighting subtle yet meaningful alterations in cardiac timing and function in the Down syndrome population. The lower VAC ratio observed in adults with Down syndrome suggests a greater reliance on ventricular compensatory mechanisms to maintain cardiac output, despite reduced diastolic blood pressure, smaller cardiac chamber dimensions, and altered systolic timing. These findings indicate a unique cardiovascular profile that may influence exercise capacity, cardiac reserve, and long-term cardiovascular health.

By integrating arterial and ventricular function measures, this study offers new insights into the dynamic cardiovascular adaptations in adults with Down syndrome and underscores the importance of looking beyond isolated metrics. Ultimately, a deeper understanding of VAC in this population may inform early screening strategies, personalized interventions, and improved cardiovascular outcomes across the lifespan of individuals with Down syndrome.

DATA AVAILABILITY STATEMENT

The data supporting this study’s findings are available from the corresponding author upon reasonable request.