Sex differences in pulmonary and systemic vascular function at rest and during exercise in healthy older adults

doi:10.21203/rs.3.rs-1981913/v1

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Sex differences in pulmonary and systemic vascular function at rest and during exercise in healthy older adults

https://doi.org/10.21203/rs.3.rs-1981913/v1

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Our aim was to conduct a sex-disaggregated analysis of pulmonary and systemic vascular function in healthy individuals both at rest and during submaximal exercise. Healthy individuals underwent right-heart catheterization at rest and during submaximal cycling. Hemodynamic data were collected in a control state and with moderate exercise. Pulmonary and systemic vascular variables including: compliance, resistance, and elastance were calculated, indexed to body surface area (BSA), adjusted for age and compared between male and female sex. Thirty-six individuals (18M/18F; 54±7 vs. 58±6 years, p=0.04) were included. When adjusted for age and indexed to BSA, total pulmonary resistance (TPulmR) (516±73 vs. 424±118 WU•m^-2, p=0.03) and pulmonary arterial elastance (PEa) (0.41±0.1 vs. 0.32±0.1 mmHg•mL^-1•m², p=0.03) were higher in females vs. males. Both pulmonary (Cpa) and systemic compliance (Csa) were lower in females vs. males however lost significance with adjustment for age. Systemic arterial elastance (SEa) was higher in females (1.65±0.29 vs. 1.31±0.24 mmHg•mL^-1, p=0.05). Secondary analyses demonstrated significant correlations between age and PVR (r=0.33, p=0.05), TPulmR (r=0.35, p=0.04), Cpa (r=-0.48, p<0.01), and PEa (r=0.37, p=0.03). During exercise, there were greater increases in TPulmR (p=0.02) and PEa (p=0.01) in females vs. males. TPulmR and PEa are significantly higher at rest and exercise in females vs. males. Cpa and Csa were lower in females, however this may have been confounded by age. Our results are consistent with the notion that indices of pulmonary and systemic vascular load are increased related to both older age and female sex.

pulmonary

systemic

hemodynamics

right heart catheterization

exercise

healthy

sexual dimorphism

heart failure with preserved ejection fraction

What is known about topic?

Female sex is associated with increased arterial stiffening with age
Increased arterial stiffness translates to greater pulsatile afterload and can predispose to the development of hypertension and diastolic dysfunction.
Pulmonary and systemic arterial compliance are lower in females during both rest and exercise.

What this study adds?

At rest systemic and pulmonary compliance are lower and pulmonary effective elastance is higher in healthy middle-aged females when compared to males.
There is a relationship between pulmonary vascular characteristics and age, independent of sex.
Higher systemic and pulmonary vascular loading observed in healthy female sex may be a contributing factor to the increased prevalence of hypertension and HFpEF in females.

Exercise capacity declines with age, however, the mechanisms underlying this age-associated decline may be different between male and female sex.^1,2 Age-related ventricular-vascular stiffening likely predisposes to several conditions including hypertension, the development of heart failure with preserved ejection fraction (HFpEF) and associated exercise intolerance.³ Importantly, female compared to male sex is also associated with increased arterial stiffening with aging.^1,2 This sex-specific effect has been demonstrated non-invasively via echocardiography in community-based studies, even in the absence of cardiovascular disease, however this has not been thoroughly evaluated with invasive hemodynamic measurements.⁴ This increase in arterial stiffness translates to greater pulsatile afterload and can predispose to the development of hypertension and diastolic dysfunction.^5,6 It is well established that hypertension is more prevalent in female patients with HF and that hypertension increases the risk of developing HF by 3-fold in women, compared to 2-fold in men.⁷ This construct may explain the female predilection that has been observed in HFpEF.^8,9 More recently, it was demonstrated that among patients with HFpEF, greater arterial stiffness, both at rest and during exercise, was observed in females and was related to evidence of abnormal pulmonary artery wedge pressure (PAWP) responses to exercise.¹⁰ These investigators further demonstrated that both pulmonary and systemic arterial compliance were lower in females during both rest and exercise.¹⁰

It has been hypothesized that sex differences observed in disease states may be rooted in sexual dimorphism observed in health.^11,12 Such differences may influence susceptibility in the presence of a disease accelerator, or the timing of disease onset. Therefore, we undertook the current study to evaluate invasively measured pulmonary and systemic vascular hemodynamics at rest and during exercise in healthy, middle-aged females and males, free of comorbid conditions or risk factors that influence vascular health. We aimed to describe the range of these invasively measured indices in healthy humans, and to conduct a sex-disaggregated analysis.

Subjects

Healthy, untrained males and females ≥ 45 years old were recruited from the community as previously described.¹³ Hemodynamic data from this cohort has previously been published;¹³ although blood pressure and resistive load were presented, they were not specifically focused on, and the vascular load was not comprehensively characterized in pulsatile and total terms. All subjects completed a medical history, blood pressure measurement, 12-lead electrocardiogram, and standard echocardiography. Exclusion criteria were a history of cardiovascular disease or cardioactive drug use, recent smoking, diabetes, and pre-menopausal status in females. Further exclusion criteria were a seated blood pressure > 140/90 mmHg, body mass index > 30 kg/m², LV mass index > 88/102 g/m² (female/male), valvular disease, non-sinus rhythm, diabetes mellitus, or other chronic disease. The study was approved by the Mount Sinai Hospital research ethics board, conducted in accordance with the Declaration of Helsinki, and all participants provided written, informed consent.

Experimental procedures: Right heart catheterization and exercise

Right heart catheterization (RHC) was performed via ultrasound-guided cannulation of the upper arm.^13,14 A 7Fr, multi-lumen, fluid-filled flotation catheter (Edwards Life-sciences) was placed and pressure transducers were zeroed at the mid-axillary level. Simultaneous right atrial (RA) and pulmonary artery (PA) pressures were recorded continuously and PAWP was recorded intermittently for offline analysis (300Hz; MacLab v6.5, GE Healthcare). Mixed venous blood was sampled for oximetry, and Fick cardiac output (CO) was estimated. Initial measurements were obtained in the supine position (Baseline). Subjects were then transferred to a cycle ergometer (Ergoselect 1200E, Ergoline), and were studied in a semi-upright position under two conditions: Control, quiet rest in semi-upright, cycling position; and Moderate, exercise at a target heart rate of 120 bpm for 8–10 min. At each condition, blood pressure was measured by an automated auscultatory sphygmomanometer (Tango+, SunTech), and balloon inflation was performed to acquire the PAWP for ≥ 10 cardiac cycles over 2–3 respiratory cycles. Mixed venous blood was sampled for oximetry, and CO was measured by thermodilution in triplicate within ≤ 10% variation.

Hemodynamic data analysis

For each condition, mean RA pressure, systolic/diastolic/mean PA pressure (PASP/PADP/mPAP), and PAWP was measured at visually confirmed end-expiration, as previously described.^13–15 Stroke volume (SV, mL) was calculated from thermodilution measures as [CO/heart rate].

Calculated Pulmonary and Systemic Vascular Endpoints

Calculated pulmonary vascular endpoints included the transpulmonary pressure gradient (TPG, mmHg = [mPAP – mean PAWP]) and pulmonary vascular resistance (PVR, d•s•cm^− 5 = WU = [TPG/CO]). The PA pulse pressure (mmHg = [PASP – PADP]) and pulmonary arterial compliance (Cpa, mL•mmHg^− 1 = [SV/PA pulse pressure]) were calculated, as was the product of PVR and Cpa [RC-time, s = (TPG/PA pulse pressure)×(60/heart rate)]. Total pulmonary resistance (TPulmR) (mmHg•mL^− 1•s^− 1) was calculated as mPAP/CO. Systemic pulse pressure, systemic arterial compliance (Csa), systemic vascular resistance (SVR), and total peripheral resistance (TPR) were calculated using similar formulas. The lumped parameter of right ventricular (RV) afterload, pulmonary effective arterial elastance (PEa), mmHg•mL^− 1 was estimated using mPAP/SV.^16,17 RV stroke work index, a measure of RV functional capacity, was calculated as 0.0136 × SV index(mean PA pressure – RA pressure).¹⁸ Lastly, both pulmonary and systemic variables were indexed to body surface area (BSA).

Statistical Analysis

Normality was assessed using the Shapiro-Wilk test and examination of Q-Q plots. Data are presented as mean ± standard deviation or median (IQR), as appropriate. The original sample size calculation was based on detecting sex differences in physiologic variables. A sample of 18 males and 18 females would achieve a power of over 80% to detect a 25% difference in means between sexes assuming a standard deviation of approximately 25% of the mean. Participant characteristics and baseline hemodynamics were compared between males and females using Student’s t-test or Mann-Whitney U-test. Comparisons of continuous variables between exercise conditions and groups were performed using two-way repeated-measures ANOVA. Significant main effects and interactions were analyzed post hoc using Bonferonni-adjusted t-tests. Mauchly's Test was conducted to test for the assumption of sphericity. If the assumption of sphericity was violated, the Greenhouse-Geisser correction was employed to determine significant main effects. Statistical analyses were performed using SPSS Version 24 (IBM Inc.). In addition, adjustments were made for age and between group effects were compared between sexes. Associations between continuous variables were conducted using bivariate correlations, as well as partial correlations when adjustments were made. A two-tailed alpha level of 0.05 was considered significant.

Analyses of the PAWP responses to exercise were previously published from this cohort.¹³ In this study, detailed measurements of pulmonary and systemic vascular function and their relationships are presented as a function of sex and adjusted for age.

Demographic and hemodynamic characteristics

Baseline participant demographics and hemodynamics are displayed in Table 1. A total of 36 (18 male/18 female) were recruited to participate in this study. Age was significantly higher in females vs. males (58 vs. 54 years, p = 0.04). Height, weight and BSA was higher in males (male; 2.0 ± 0.2 vs. female; 1.7 ± 0.1 m², p < 0.001), although BMI was not significantly different (male; 26.0 ± 3.3 vs. female; 24.8 ± 2.7 kg•m^− 2, p = 0.24). Hemoglobin was also significantly higher in males (male; 14.3 ± 1.0 vs. female; 12.9 ± 0.9 g•dL^− 1, p < 0.001), although within the clinical range of normal.

Table 1

Baseline subject characteristics and hemodynamics
	Male (n = 18)	Female (n = 18)	p value
Age (years)	54 ± 7	58 ± 6	p = 0.04
Height (cm)	176 ± 7	164 ± 6	p < 0.001
Weight (kg)	80 ± 13	67 ± 9	p = 0.001
Body Surface Area (m²)	2.0 ± 0.2	1.7 ± 0.1	p < 0.001
Body Mass Index (kg/m²)	25.9 ± 3.3	24.8 ± 2.7	p = 0.24
Hemoglobin (g/L)	142.8 ± 1.0	128.7 ± 0.9	p < 0.001
Heart Rate (bpm)	61 ± 7	63 ± 9	p = 0.46
Systolic BP (mmHg)	122 ± 12	119 ± 13	p = 0.50
Diastolic BP (mmHg)	75 ± 10	68 ± 9	p = 0.05
Stroke Volume (mL)	86 ± 12	67 ± 12	p < 0.001
Stroke Volume Index (mL/m²)	44 ± 5	39 ± 6	p = 0.015
Cardiac Output (L/min)	5.2 ± 0.7	4.2 ± 0.6	p < 0.001
Cardiac Index (L/min/m²)	2.6 ± 0.3	2.4 ± 0.4	p = 0.04
Right Atrial Pressure (mmHg)	4.7 ± 1.9	6.6 ± 2.1	p = 0.01
RVSP (mmHg)	24 ± 4	26 ± 5	p = 0.13
PASP (mmHg)	21 ± 4	23 ± 4	p = 0.21
PADP (mmHg)	7 ± 3	8 ± 2	p = 0.17
mPAP (mmHg)	14 ± 3	16 ± 3	p = 0.07
PAWP (mmHg)	9 ± 3	11 ± 3	p = 0.03

Baseline Vascular Function

Pulmonary and systemic vascular variables at Baseline are presented in Table 2. We have previously demonstrated that RA pressure and PAWP at Baseline were significantly higher in females than males and that cardiac index (male; 2.6 ± 0.3 vs. female; 2.4 ± 0.4 L•min^− 1•m^− 2, p = 0.04) is lower in females.

Table 2

Pulmonary and systemic calculations at *Baseline*.
	Male (n = 18)	Female (n = 18)
Pulmonary
Pulmonary vascular resistance (d•s•cm^− 5)	81 ± 32	95 ± 36
Pulmonary vascular resistance index (d•s•cm^− 5•m^− 2)	159 ± 63	163 ± 58
Total pulmonary resistance (d•s•cm^− 5)	214 ± 49	300 ± 42*^,#
Total pulmonary resistance index (d•s•cm^− 5•m^− 2)	424 ± 118	516 ± 73*^,#
Pulmonary pulse pressure (mmHg)	14 ± 4	15 ± 4
Pulmonary arterial compliance (mL•mmHg^− 1)	6.6 ± 2.3	4.9 ± 1.5*
Pulmonary arterial compliance index (mL•mmHg^− 1•m^− 2)	3.3 ± 1.1	2.8 ± 0.8
Pulmonary arterial elastance (mmHg•mL^− 1)	0.16 ± 0.04	0.24 ± 0.06*^,#
Pulmonary arterial elastance index (mmHg•mL^− 1•m²)	0.32 ± 0.08	0.41 ± 0.10*^,#
RC-time (s)	0.38 ± 0.17	0.32 ± 0.08
Systemic
Systemic pulse pressure (mmHg)	48 ± 9	52 ± 12
Systemic vascular resistance (d•s•cm^− 5)	1369 ± 267	1459 ± 271*^,#
Systemic vascular resistance index (d•s•cm^− 5•m^− 2)	2620 ± 426	2407 ± 439
Total peripheral resistance (d•s•cm^− 5)	1407 ± 208	1707 ± 307*^,#
Total peripheral resistance index (d•s•cm^− 5•m^− 2)	2707 ± 467	2927 ± 455
Systemic arterial compliance (mL•mmHg^− 1)	1.9 ± 0.4	1.3 ± 0.3*^,#
Systemic arterial compliance index (mL•mmHg^− 1•m^− 2)	1.0 ± 0.2	0.8 ± 0.2*
Systemic arterial elastance (mmHg•mL^− 1)	1.31 ± 0.24	1.65 ± 0.29*^,#
Systemic arterial elastance index (mmHg•mL^− 1•m²)	2.56 ± 0.44	2.82 ± 0.45
*Mean ± SD. Significance for comparison of male vs. female p < 0.05, ^#adjusted for age p < 0.05**

Pulmonary Hemodynamics

There was no difference in PVR between females and males. On the other hand, TPulmR was significantly higher in females, even when indexed to BSA (Table 2, Fig. 1), or when adjusted for age. Cpa was significantly lower in females, as demonstrated in Fig. 1, however this was no longer the case when indexed to BSA and adjusted for age. Although Cpa was lower in females, the product of PVR and Cpa (RC-time) was not significantly different. PEa was also significantly higher in females when compared to males, which remained significant when indexed to BSA, and adjusted for age. RV stroke work index was similar between males and females. In addition, there were significant relationship between age and PVRI, TPulmRI, CpaI, and PEaI (Fig. 3).

Systemic Variables

SVR and TPR were significantly higher in females vs. males, however these differences were no longer present when indexed to BSA. Similar to Cpa, Csa was significantly lower in healthy middle-aged females vs. males, which remained significant when indexed to BSA (p = 0.01) but lost significance when adjusted for age (p = 0.08) (Fig. 2). SEa was also higher in females vs. males which remained significant after adjusting for age (p = 0.05), however lost significance when indexing to BSA (p = 0.39). Age based analysis demonstrated a significant relationship between age and CsI and SEaI but not TPR or SVR (Fig. 3).

Exercise Responses

We have previously demonstrated that the exercise work-rate, CO, and SV responses to exercise are lower in females than males. Also, there were no differences in the exercise responses with respect to RA, PA, and PAWP.¹³

Pulmonary Hemodynamics

Pulmonary hemodynamics during Control and Moderate exercise are displayed in Table 3. In both males and females, there was a reduction in Cpa with exercise, with the values in females trending towards being lower, however this did not reach statistical significance. There was a greater decline in TPulmR in males when compared to females from control to moderate exercise and the increase in pulmonary effective arterial elastance was greater in females versus males.

Table 3

Pulmonary and systemic calculations at control and during moderate exercise.
		Control	Moderate
Work-rate (W)	Male	-	82 ± 21*
	Female	-	53 ± 23*
Heart rate (bpm)	Male	62 ± 7	121 ± 2
	Female	64 ± 8	122 ± 3
Cardiac index (L•min^− 1•m^− 2)	Male	2.8 ± 0.6	6.6 ± 1.9
	Female	2.5 ± 0.4	5.4 ± 1.8
Stroke volume index (mL•m^− 2)	Male	45 ± 11	55 ± 16
	Female	39 ± 8	47 ± 10
Pulmonary
Mean pulmonary arterial pressure (mmHg)	Male	17 ± 3	25 ± 6
	Female	18 ± 2	26 ± 6
Pulmonary pulse pressure (mmHg)	Male	14 ± 3	23 ± 6
	Female	14 ± 3	21 ± 5
Pulmonary vascular resistance (d•s•cm^− 5)	Male	104 ± 35	91 ± 34
	Female	119 ± 49	96 ± 26
Total pulmonary resistance (d•s•cm^− 5)	Male	271 ± 49	172 ± 46*
	Female	309 ± 38	201 ± 49*
Pulmonary arterial compliance (mL•mmHg^− 1)	Male	6.0 ± 1.7	4.8 ± 2.0
	Female	5.3 ± 1.4	4.2 ± 1.2
Pulmonary effective arterial elastance (mmHg•mL^− 1)	Male	0.21 ± 0.04	0.26 ± 0.07*
	Female	0.25 ± 0.04	0.31 ± 0.07*
Systemic
Mean arterial pressure (mmHg)	Male	98 ± 8	112 ± 8
	Female	95 ± 10	108 ± 9
Systemic pulse pressure (mmHg)	Male	47 ± 9	93 ± 14
	Female	50 ± 15	84 ± 16
Systemic vascular resistance (d•s•cm^− 5)	Male	1504 ± 294	747 ± 244
	Female	1595 ± 261	797 ± 127
Total peripheral resistance (d•s•cm-⁵)	Male	1594 ± 302	786 ± 248
	Female	1711 ± 267	854 ± 124
Systemic arterial compliance (mL•mmHg^− 1)	Male	1.8 ± 0.50	0.92 ± 0.28
	Female	1.5 ± 0.57	0.79 ± 0.12
Systemic arterial elastance (mmHg•mL^− 1)	Male	1.5 ± 0.35	1.7 ± 0.51
	Female	1.7 ± 0.29	1.8 ± 0.24
*Mean ± SD. Significance for comparison of between-subjects effects (male vs. female) for changes in exercise p < 0.05**

Systemic Hemodynamics

On the systemic side, there was a reduction in Csa and SVR in both males and females with increasing exercise however there were no significant between-sex differences in vascular parameters with exercise.

This study aimed to evaluate sex differences in pulmonary and systemic vascular hemodynamics assessed by RHC at rest and during exercise in otherwise healthy individuals. In the pulmonary circuit, we observed significantly greater TPulmR as well as significantly lower CPa in females when compared to males at rest. Similarly, CSa was significantly lower in females when compared to males. Both pulmonary and systemic effective arterial elastance were also higher at rest in females compared to males. These findings may help to contextualize the hemodynamics of systemic and pulmonary ventricular-vascular units measured in disease states, by contributing uncommonly available physiologic data from healthy humans. In addition to the sex-based comparisons, even amongst the narrow age range of subjects recruited in this study, we were able to demonstrate relationships between both systemic and pulmonary vascular pulsatile loading and age. The recruitment criteria for this study resulted in a cohort of individuals with similar BMI without significant comorbidities which minimized the requirement to adjust for confounding variables.

In the systemic circuit, we identified lower Csa and increased SEa in females. These findings are consistent with increased arterial stiffness and higher arterial pulsatile loading in females, supportive of data reported by other investigators using non-invasive methodology.¹¹ It has been hypothesized that the female predilection of HFpEF is based on the interaction between sex and aging on ventricular-vascular coupling and higher systemic pulsatile loading. Our data confirms that even in a healthy cohort of individuals within a narrow age range, females have markers of higher arterial load and that there is also a detectable effect of age. The predisposition to HFpEF is likely multi-factorial and related to chronic exposure to several pathologic features that are also affected by sex.¹⁹ Our findings are consistent with the notion that both age and female sex increase vulnerability when exposed to risk factors that accelerate vascular stiffening such as hypertension or obesity.⁹

We examined several measures of pulmonary vascular function, including the calculation of pulmonary effective arterial elastance, which has been referred to as a “lumped” parameter of RV afterload.¹⁶ It is a summative measure representative of the resistive load across the pulmonary vasculature, the pulsatile load in systole and related downstream influence of the PAWP. Our data showed pulmonary effective arterial elastance was significantly greater in females. This appeared to be related to higher pulsatile afterload as Cpa was lower in females, while in contrast, resistive load across the pulmonary vasculature was not different between females and males.²⁰ Lam et al have provided evidence that links higher pulmonary artery pressure in older adults to evidence of systemic arterial stiffening.²¹ Our observations of systemic and pulmonary vascular characteristics are supportive of this notion particularly in females, but the cross sectional nature precludes assumptions of causality.

During exercise, as expected, SVR declined as did Csa without significant differences between males and females. As we have previously reported, Cpa declined steadily with increasing exercise effort¹⁵ with only a trend to lower Cpa at each exercise stage in females. The analysis further demonstrates that sex does not alter the relationship between PVR and Cpa during dynamic exercise, as the behaviour of the RC-time product was similar between males and females. Although we observed sex differences in resting measures of vascular resistance and compliance, with the stimulus of exercise, sex differences were not as discernible. However, effective pulmonary elastance remained higher in females suggesting higher RV afterload persists in females with exercise.

Although we recruited individuals within a narrow range of age (45-74y), secondary analyses still demonstrated significant relationships between age and both pulmonary and systemic compliance and elastance indices. This confirms, using invasive hemodynamic measurements, the findings of other investigators that large artery stiffness increases, or becomes less compliant with age in both the pulmonary and the systemic circulation.^4,21 In this study, our lower age range was confined to age > 45 years as changes in arterial properties are likely not linear over the lifespan. In both sexes, there may be effects of changing sex steroid hormone status, and possibly the subclinical onset of vascular risk factors. Our findings are relevant to the hypothesized role of increased arterial stiffness in pathologic conditions, such as HFpEF and are consistent with the observed predilection of females to both increased stiffness and HFpEF.^5,10 A recent study by Lau et al. demonstrated that amongst individuals with HFpEF, females have significantly higher measures of arterial stiffness than males, in addition to abnormal steep increases in PAWP during exercise. They assessed arterial stiffness via augmentation pressure and index as well as aortic pulse pressure. They also demonstrated that these measures of arterial stiffness were associated with a greater PAWP/CO slope, with a higher odds ratio in females, suggesting higher indices of arterial stiffness with exercise. The current study provides further evidence for increased stiffness in healthy females compared to males as estimated by systemic and pulmonary compliance derived from right heart catheterization. This is in line with the concept that even healthy middle-aged females sustain chronic exposures of both the RV and LV to stiffer vasculatures which, in turn may contribute towards the development of HFpEF with aging.¹⁹

In this study, we should acknowledge that the calculation of compliance or elastance and resistance are highly dependent on measurement of SV and CO, respectively, which in turn are systematically different between males and females. Other methods to assess vascular compliance employ assessment of the geometric changes in systole and diastole,²² but are also affected by baseline differences in vessel size. Measures of vascular resistance were expressed indexed to body surface area, as well as height.¹³ Even so, such adjustments remain affected by systematic sex differences in body habitus, not necessarily reflected in weight or height. As noted, our findings, at least with respect to Csa and SVR, are in agreement with other investigators employing different techniques of measurement.^5,16 For investigations using similar RHC methods, the current data highlight the need to contextualize measurements with sex specific comparator controls and if possible, obtain supporting evidence using other methods.

Limitations

There are several limitations to our analysis. Based on the invasive methods, we assessed a relatively small sample of healthy individuals and may have been underpowered to compare the vascular measurements. The original investigation was powered to evaluate exercise changes in PAWP between males and females, and in fact we did observe baseline differences in PCWP. There are inherent drawbacks to the use of fluid-filled catheters, with respect to wave reflection and the time response. The limitations of the calculations employed for compliance and resistance were noted. The estimation of Cpa assumes that the proximal pulmonary arteries are exposed to the entire SV in a closed system and does not take into account the volume leaving the pulmonary circulation during exercise.^20,23,24 Pulmonary effective arterial elastance was calculated using the ratio of mPAP to SV, which assumes the RV pressure at end-diastolic volume equals zero.²⁵ In addition, there was a difference in age between our two groups, although this was accounted for by adjusting all variables for age.

This study contributes quantitative information showing at rest, invasively-measured Cpa and Csa are lower in a group of healthy, middle-aged females compared to males. In addition, pulmonary effective arterial elastance, as a lumped parameter of RV afterload, is also higher amongst females. The inter-relationships between PAWP, PVR, and Cpa are similar at rest and with exercise between males and females, however there appears to be a relationship with age, independent of sex. This study supports the concept that higher systemic and pulmonary vascular loading, detectable even in healthy females, is a factor contributing to the greater strength of the association between hypertension and the development of HFpEF in females compared to males.

ACKNOWLEDGEMENTS

None.

FUNDING

The authors received no financial support for the research, authorship, and/or publication of this article.

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

AUTHORS’ CONTRIBUTIONS

RTS, SPW, and SM contributed to the acquisition, analysis, or interpretation of data for the work. RTS drafted the manuscript. SPW, RFB, FHV and SM critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

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There is NO conflict of interest to disclose.

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Sex differences in pulmonary and systemic vascular function at rest and during exercise in healthy older adults

Status:

Version 1

Abstract

Figures

SUMMARY

Introduction

Methods

Subjects

Experimental procedures: Right heart catheterization and exercise

Hemodynamic data analysis

Statistical Analysis

Results

Demographic and hemodynamic characteristics

Baseline Vascular Function

Pulmonary Hemodynamics

Systemic Variables

Exercise Responses

Pulmonary Hemodynamics

Systemic Hemodynamics

Discussion

Limitations

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1