Sex Differences in Right Ventricular, Pulmonary Vascular, and Integrated Hemodynamic Measures of Cardiac Function in HFpEF and HFrEF

Abstract

Background

Sex differences in clinical presentations of heart failure (HF) are pervasive, yet differences in invasive hemodynamic measures across HF subtypes remain incompletely characterized. Understanding these distinctions is critical, as sex‐specific physiology influences disease progression and prognostic assessment in HF.

Methods

We conducted a retrospective cohort study of 1818 patients with HF who underwent clinically indicated right heart catheterization, stratified by preserved versus reduced ejection fraction. We examined the association of sex with invasive hemodynamic measures of right ventricular, pulmonary vascular, and left ventricular function using multivariable linear regression.

Results

We studied n=709 individuals with heart failure with preserved ejection fraction (HFpEF) (44% women, mean age 68±10 years) and n=1109 with heart failure with reduced ejection fraction (HFrEF) (26% women, mean age 64±12 years). Women and men had similar measures of right ventricular function across HF subtypes (multivariable‐adjusted P>0.05 for all). However, women with both HFpEF and HFrEF exhibited worse pulmonary vascular function, with significantly higher pulmonary vascular resistance and lower pulmonary artery compliance (multivariable‐adjusted P<0.001). Women with both HFpEF and HFrEF had similar cardiac power index, but higher aortic pulsatility index (P=0.01 for HFpEF; P<0.001 for HFrEF).

Conclusions

Among a large hospital‐based sample of patients with HF, women and men exhibited similar indices of right ventricular function, despite women having worse pulmonary vascular function. Cardiac power index was similar between sexes in both HFpEF and HFrEF, whereas aortic pulsatility index was higher in women with HFrEF. Taken together, sex differences in hemodynamic measures were largely similar across individuals with HFpEF and HFrEF. Future studies are needed to delineate clinical implications of these sex differences.

Nonstandard Abbreviations and Acronyms

API

aortic pulsatility index

CI

cardiac index

CPI

cardiac power index

CPO

cardiac power output

Ea

pulmonary effective arterial elastance

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

PAC

pulmonary arterial compliance

PAPi

pulmonary artery pulsatility index

PCWP

pulmonary capillary wedge pressure

RA

right atrial

RVSWI

right ventricular stroke work index

SV

stroke volume

SVI

stroke volume index

Clinical Perspective.

What Is New?

• In a large hospital‐based cohort of patients with heart failure with preserved ejection fraction and heart failure with reduced ejection fraction, women and men exhibited similar right ventricular function, despite women demonstrating worse pulmonary vascular function and higher aortic pulsatility index.

What Are the Clinical Implications?

• Recognition of these sex differences in hemodynamic abnormalities may help better understand well‐described clinical differences among women and men with heart failure.

Sex differences in cardiovascular physiology are well‐described and may underlie distinct predisposition, clinical presentation, and hemodynamic manifestations of heart failure (HF) among women versus men. For instance, in patients with heart failure with preserved ejection fraction (HFpEF), women have worse diastolic reserve compared with men, as evidenced by greater elevations in pulmonary capillary wedge pressure (PCWP) indexed to workload and higher mitral E/e′ ratio both at rest and during exercise. ¹ , ² In addition, women with HFpEF typically have lower cardiac output (CO) and lower stroke volume reserve compared with men. ¹

Whether these sex differences extend to other invasive hemodynamic measures that reflect right ventricular (RV) function and pulmonary vascular (PV) function in the context of HF remains unclear. Further, little is known about sex differences that may be shared versus distinct among individuals with HF with preserved versus reduced ejection fraction. Lastly, emerging integrated metrics—such as cardiac power index (CPI) and aortic pulsatility index (API)—have been recently used to assess cardiac performance in the setting of cardiogenic shock and advanced HF. ³ , ⁴ Higher CPI reflects better cardiac performance and portends improved survival, even after adjustment for conventional metrics such as PCWP and ejection fraction. ³ Lower API is independently associated with progression to advanced therapies or death, with superior predictive value compared with CO. ⁴ However, the prognostic utility and sex differences in these integrated indices among less critically ill HF patients remain unclear.

In this study, we sought to comprehensively characterize invasive hemodynamic measures in a broad hospital‐based sample of individuals with HFpEF versus HFrEF. We specifically investigated sex differences across hemodynamic measures of RV, PV, and left ventricular (LV) function, incorporating both traditional and novel integrated measures. Given the central role of hemodynamic measures in therapeutic decision‐making and prognosis, elucidating sex‐based differences in invasive hemodynamic measures stratified by HF subtype has the potential to refine risk stratification and shed further light into well‐described sex differences across clinical presentation and outcomes in HF.

METHODS

Statistical code and analytic methods will be made available from the corresponding author upon request. The data are not available to other researchers for purposes of reproducing the results. Informed consent was not required/waived.

Study Sample

We studied consecutive ambulatory and hospitalized patients who underwent clinically indicated right heart cathterization (RHC) at Massachusetts General Hospital between 2005 and 2016. Among individuals with multiple procedures, only the initial RHC was included. Of the 10 306 cases identified, we excluded individuals with acute myocardial infarction (MI) on the day of catheterization, cardiac arrest or shock within 24 hours, mechanical ventilation, intra‐aortic balloon pump, history of heart or lung transplant, complicated adult congenital heart disease, prior valvular replacement, or dialysis dependence (n=887). We also excluded cases with missing key clinical covariates (n=484), missing patient identifiers (n=398), or missing hemodynamic data (n=252), resulting in 8285 individuals. Of these 8285 individuals, 2062 had clinical HF, and had echocardiography within 1 year of RHC to classify HF into HFpEF (LVEF≥50%) versus HFrEF (LVEF<50%). From this group, we further excluded individuals with missing critical hemodynamic variables—yielding a final study sample of 1818 participants. A secondary sample of 1162 participants was derived after further excluding those with missing data on variables CPO and API. This study was approved by the appropriate Institutional Review Boards.

Clinical and Echocardiographic Assessment

Clinical characteristics were obtained from medical records at the time of RHC and included age, sex, body mass index (BMI), smoking status, and the presence of comorbidities such as chronic kidney disease, diabetes, hypertension, hypercholesterolemia, chronic lung disease, obstructive sleep apnea (OSA), history of MI and valvular disease. OSA was identified using, Ninth and Tenth Revision (ICD‐9 and ICD‐10) codes from the electronic medical record. Multimorbidity was defined as the presence of 2 or more chronic health conditions, and included obesity, chronic kidney disease, diabetes, hypertension, prior lung disease, OSA, and history of MI. ⁵ Echocardiographic data within one year of RHC were reviewed to extract both quantitative and qualitative assessments of LV size and function. When multiple echocardiograms were available within one year of RHC, the study performed closest to the catheterization date was used. LV hypertrophy was defined using sex‐specific thresholds for LV mass index, with values >95 g/m² for women and >115 g/m² for men, in accordance with established clinical criteria. ⁶ , ⁷

Invasive Hemodynamic Assessment Via RHC

Key hemodynamic parameters recorded at the time of RHC included resting blood pressure, heart rate (HR), mean right atrial (RA) pressure, pulmonary artery (PA) systolic and diastolic pressure, and mean PCWP. CO and cardiac index (CI) measurements were primarily obtained using the thermodilution method; when unavailable, the assumed Fick cardiac output and index were used. Both were indexed using the Mosteller formula for body surface area (BSA). ⁸ SV was calculated as CO divided by HR, and SV index (SVI) was indexed to BSA. Non‐physiologic values were set to missing (<1% of measurements).

We examined the following hemodynamic indices of RV function: RA/PCWP ratio, a surrogate of RA pressure relative to left‐sided filling pressure, RVSWI (RVSWI=0.0136×SVI×[mean PA–RA pressure]), an estimate of RV contractile work; and PA pulsatility index (PAPi=[PA systolic–PA diastolic pressure]/RA) integrated preload and afterload to characterize RV‐pulmonary artery coupling. For PAPi, RA was imputed as 1 if listed as 0. We additionally examined pulmonary effective arterial elastance/RA pressure (Ea/RA pressure=[mean PA pressure–PCWP]/[SV×RA pressure]) as a reflection of PV load and right‐sided congestion. ⁹ , ¹⁰ We evaluated the following PV indices: PVR (PVR=([mean PA pressure–PCWP]/CO)×80), transpulmonary gradient (TPG=mean PA pressure–PCWP), and PA compliance (PAC=SV/[PA systolic–PA diastolic pressure]). Lastly, integrated measures of cardiac function were calculated among a subset of n=1162 (64%) of individuals who had available matched blood pressure data, which included cardiac power output (CPO=CO×mean arterial pressure [MAP]/451), CPI (CPI=[MAP×CI]/451) and API (API=[systolic–diastolic pressure]/PCWP). ³ , ¹¹

Statistical Analysis

Baseline clinical, echocardiographic, and hemodynamic characteristics were summarized by HF subtype and stratified by sex. Distributions of hemodynamic variables were examined, natural log‐transformed if skewed, and standardized to a mean of 0 and SD of 1. To minimize the influence of outliers, the distributions of RA/PCWP ratio and PAPi were winsorized. For RA/PCWP, values were limited to a range of 0.1 to 3.5; for PAPi, values were bounded at a minimum of 0.3 and a maximum of 30 as in prior studies. ¹²

We pre‐specified 6 primary hemodynamic measures including RA/PCWP ratio, PAPi, PVR, PAC, CPI, and API. In separate analyses for HFpEF and HFrEF, we examined cross‐sectional associations of sex with hemodynamic variables using multivariable linear regression models. The model first accounted for age, and additionally for other comorbidities including BMI, chronic kidney disease, diabetes, hypertension, chronic lung disease, OSA, and prevalent MI. For indexed values including RVSWI, CI, SVI, and CPI, analyses were adjusted for age and comorbidities but not BMI or BSA. Exploratory analyses adjusted non‐indexed measures for BSA in place of BMI. To account for multiple comparisons, we applied a Bonferroni correction, setting the statistical significance threshold at P value <0.008, with suggestive P<0.05. All analyses were performed using STATA software, Version 18.5 (College Station, Texas).

RESULTS

A total of 709 individuals with HFpEF (mean age 68±10 years, 44% women), and 1109 individuals with HFrEF (mean age 64±12 years, 26% women) were included in the study. Baseline clinical and echocardiographic characteristics, stratified by sex for both HFpEF and HFrEF, are presented in Table 1, with baseline characteristics for the subsample of n=1162 with available CPO and API presented in Table S1.

Table 1.

Sex Differences in Clinical and Echocardiographic Characteristics Among Individuals With HFpEF Versus HFrEF

	HFpEF			HFrEF
	Women	Men	P value	Women	Men	P value
	(n=311)	(n=398)		(n=289)	(n=820)
Clinical characteristics
Age, y	68±10	68±10	0.81	64±12	64±12	0.92
Race, n (%) White	272 (87)	351 (88)	0.33	222 (77)	676 (82)	0.22
Black	9 (3)	11 (3)		19 (7)	46 (6)
Hispanic	8 (3)	9 (2)		14 (5)	33 (4)
Asian	8 (3)	3 (1)		6 (2)	16 (2)
Unknown	14 (5)	24 (6)		28 (10)	49 (6)
BMI, kg/m2	31.2±8.6	30.2±6.1	0.08	28.2±7.6	28.9±6.3	0.13
NYHA Class, n (%) I	4 (3)	10 (5)	0.08	1 (1)	15 (4)	0.16
II	39 (27)	76 (37)		35 (22)	76 (20)
III	87 (60)	95 (47)		87 (56)	226 (59)
IV	15 (10)	22 (11)		33 (21)	69 (18)
Current smoker, n (%)	19 (11)	23 (10)	0.70	21 (12)	75 (18)	0.11
Chronic kidney disease, n (%)	14 (5)	39 (10)	0.008	14 (5)	43 (5)	0.79
Diabetes, n (%)	110 (35)	170 (43)	0.047	101 (35)	298 (36)	0.67
Hypertension, n (%)	243 (78)	318 (80)	0.57	186 (64)	616 (75)	<0.001
Hypercholesterolemia, n (%)	235 (80)	323 (86)	0.040	211 (76)	666 (83)	0.012
Chronic lung disease, n (%)	102 (33)	96 (24)	0.011	65 (22)	141 (17)	0.047
OSA, n (%)	48 (15)	95 (24)	0.006	19 (7)	116 (14)	<0.001
Previous MI, n (%)	58 (19)	110 (28)	0.005	95 (33)	403 (49)	<0.001
Previous valvular disease, n (%)	186 (60)	227 (57)	0.46	136 (47)	302 (37)	0.002
Heart rate, bpm	71±15	69±14	0.039	78±16	74±15	0.003
NT‐proBNP, pg/mL*	1740 [689–3864]	1369 [504–3287]	0.09	3406 [1531–7436]	3322 [1368–7452]	0.56
Hemoglobin, g/dL	12.0±1.8	12.1±2.4	0.70	12.7±3.7	12.9±2.2	0.75
Multimorbidity, n (%)	209 (67)	297 (75)	0.03	186 (64)	584 (71)	0.03
Echocardiographic measures
LVEF, %	66 [59–73]	64 [57–70]	<0.001	30 [23–40]	26 [20–35]	<0.001
LA diameter, mm	43 [39–47]	46 [42–50]	<0.001	42 [39–45]	46 [43–50]	<0.001
LVEDD, mm	44 [40–49]	49 [44–53]	<0.001	53 [48–60]	60 [54–65]	<0.001
IVS, mm	11 [10–13]	13 [11–14]	<0.001	10 [8–11]	11 [9–12]	<0.001
PWT, mm	11 [9–12]	12 [10–13]	<0.001	10 [8–11]	10 [9–12]	<0.001
LV mass index, g/m2 †	95 [77–111]	108 [91–130]	<0.001	113 [94–134]	127 [104–152]	<0.001
RV dilation‡	43 (14)	76 (19)	0.06	46 (16)	271 (33)	<0.001
RV systolic dysfunction‡	21 (7)	41 (10)	0.10	90 (31)	389 (47)	<0.001
RVSP§	48 [41–62]	45[38–58]	0.02	46 [38–55]	46 [37–57]	0.76

Table displays mean±SD and median (interquartile range). Multimorbidity was defined as the presence of 2 or more chronic health conditions in an individual. BMI indicates body mass index; IVS, interventricular septum; LA, left atrial; LV, left ventricle; LVEDD, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA Class, New York Heart Association Functional Classification; OSA, obstructive sleep apnea; MI, myocardial infarction; PWT, posterior wall thickness; and RVSP, right ventricular systolic pressure.

^*NT‐proBNP available in 74% of participants.

^† LV mass index available in 1803 participants.

^‡ RV dilation is available in 1790 participants.

^§ RVSP is available in 1458 participants.

Among individuals with HFpEF, women and men had similar age (68±10 versus 68±10 years), BMI (31.2±8.6 versus 30.2±6.1 kg/m²), prevalence of hypertension (78% versus 80%) and prior valvular disease (60% versus 57%, P>0.05 for all). Differences in comorbidities were observed, with certain conditions being more prevalent among men compared with women, such as chronic kidney disease (5% versus 10%), diabetes (35% versus 43%), hypercholesterolemia (80% versus 86%), OSA (15% versus 24%), and prior MI (19% versus 28%). By contrast, chronic lung disease was more prevalent among women (33% versus 24%; P<0.05 for all).

Among individuals with HFrEF, women and men had similar age (64±12 versus 64±12 years), BMI (28.2±7.6 versus 28.9±6.3 kg/m²), and prevalence of chronic kidney disease (5% versus 5%) and diabetes (35% versus 36%, P>0.05 for all). Men had higher prevalence of hypertension (75% versus 64%), hypercholesterolemia (83% versus 76%), OSA (14% versus 7%), previous MI (49% versus 33%), but lower prior valvular disease (37% versus 47%, P<0.05 for all).

Among individuals with HFpEF, men had greater multimorbidity compared with women (defined as 2 or more comorbid conditions, 75% versus 67%). Similarly, among individuals with HFrEF, men had greater multimorbidity than women (71% versus 64%; P<0.05 for both).

Sex Differences in Echocardiographic Measures of Cardiac Structure and Function

Across both HF subtypes, we found that women had smaller LV dimensions and LV mass index compared with men. In addition, women had higher LVEF compared with men. Specifically, among those with HFpEF, the median LVEF was 66% [IQR 59%–73%] versus 64% [IQR 57%–70%], in women versus men, respectively; Similarly, among women with HFrEF, the median LVEF was 30% [IQR 23%–40%] versus 26% [IQR 20%–35%] in men. The prevalence of LV hypertrophy among women with HFpEF was higher than men (50% in women versus 41% in men, P=0.015). In contrast, among individuals with HFrEF, 74% of women and 65% of men met LV hypertrophy criteria (P=0.003).

Regarding RV function, there was a borderline difference in the prevalence of RV dilation (19% versus 14%, P=0.06) between men and women with HFpEF, although this did not reach statistical significance. RV systolic dysfunction (10% versus 7%, P=0.10) was similar between sexes. By contrast, more men than women had RV dilation and dysfunction among individuals with HFrEF (33% versus 16%, P<0.001 for RV dilation, 47% versus 31%, P<0.001 for RV dysfunction).

Sex Differences in Hemodynamic Parameters in HFpEF

Absolute values of primary hemodynamic parameters by HF subtype and sex are presented in Table S2. In multivariable analyses adjusting for BMI and comorbidities (Figure1Figure, Table 2), we found that among individuals with HFpEF, RV measures (RA/PCWP ratio, RVSWI, PAPi) did not differ significantly by sex (P>0.05 for all), whereas Ea/RA pressure was higher in women (β=0.30, SE=0.08, P<0.001). When using a clinical cut point of PAPi<1.85, 15% of women and 14% of men met RV dysfunction criteria (P=0.71). ¹³ Women with HFpEF had worse PV function compared with men, including higher mean PA pressure (β=0.15, SE=0.07), PVR (β=0.38, SE=0.08), transpulmonary gradient (β=0.24, SE=0.08), and lower PAC (β=−0.39, SE=0.07; P<0.05 for all). With respect to LV measures, women and men had similar mean PCWP (P>0.05), with lower CO (β=−0.42, SE=0.07) and SV (β=−0.44, SE=0.07, P<0.001 for both), and similar CI and SVI (P>0.05 for both). Sex differences in CPI and API did not meet the pre‐specified significance threshold, with borderline higher CPI (β=0.25, SE=0.10, P=0.008) and API (β=0.21, SE=0.08, P=0.01) in women versus men.

Figure 1. Associations of sex with invasive hemodynamics adjusted for age and multivariable covariates.

Beta estimates represent the SD unit difference in the hemodynamic outcomes between women and men (reference group), with positive values indicating higher values in women. Multivariable model was adjusted for age, sex, BMI, chronic kidney disease, diabetes, hypertension, chronic lung disease, OSA, and prevalent MI. Variable abbreviations: API indicates aortic pulsatility index; CI, cardiac index; CO, cardiac output; CPI, cardiac power index; CPO, cardiac power output; Ea, pulmonary effective arterial elastance; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; PAC, pulmonary arterial compliance; PAP, pulmonary arterial pressure; PAPi, pulmonary artery pulsatility index; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RVSWI, right ventricular stroke work index; SV, stroke volume; SVI, stroke volume index and TPG, transpulmonary gradient.

Table 2.

Associations of Sex With Invasive Hemodynamics Adjusted for Age, BMI, and Comorbidities

	HFpEF			HFrEF
	Beta	SE	P value	Beta	SE	P value
RV measures
Mean RA pressure, mm Hg†	−0.01	0.07	0.86	−0.11	0.07	0.09
RA/PCWP ratio	−0.03	0.07	0.66	−0.03	0.07	0.67
RVSWI, g·m/m2 *	0.12	0.08	0.13	−0.02	0.07	0.72
PAPi, mm Hg/m2 †	0.10	0.07	0.17	0.08	0.07	0.25
Ea/RA pressure, L−1	0.30	0.08	<0.001	0.35	0.06	<0.001
PV measures
Mean PA pressure, mm Hg	0.15	0.07	0.035	−0.06	0.07	0.41
PVR, woods units†	0.38	0.08	<0.001	0.32	0.07	<0.001
TPG, mm Hg	0.24	0.08	0.004	0.12	0.06	0.05
PAC, mL/mm Hg†	−0.39	0.07	<0.001	−0.25	0.07	<0.001
LV measures
Mean PCWP, mm Hg	0.01	0.07	0.92	−0.17	0.07	0.02
CO, L/min	−0.42	0.07	<0.001	−0.36	0.06	<0.001
CI, L·min−1·m−2 *	0.04	0.08	0.61	0.02	0.06	0.72
SV, mL	−0.44	0.07	<0.001	−0.39	0.06	<0.001
SVI, mL·m−2 *	−0.03	0.08	0.72	−0.08	0.06	0.18
CPO, W	−0.18	0.09	0.043	−0.21	0.08	0.007
CPI, W/m2 * , †	0.25	0.1	0.008	0.16	0.08	0.049
API†	0.21	0.08	0.01	0.42	0.09	<0.001

RA/PCWP, PAPi, PVR, PAC, CPI and API represent primary measures of interest. Beta coefficients represent the multivariable‐adjusted SD unit difference in hemodynamic parameter in women compared with men. Multivariable model was adjusted for age, sex, BMI, chronic kidney disease, diabetes, hypertension, chronic lung disease, OSA, and prevalent MI. API indicates aortic pulsatility index; CI, cardiac index; CO, cardiac output; CPI, cardiac power index; CPO, cardiac power output; Ea, pulmonary effective arterial elastance; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; PA, pulmonary artery; PAC, pulmonary arterial compliance; PAPi, pulmonary artery pulsatility index; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RA, right atrial; RVSWI, right ventricular stroke work index; SV, stroke volume; SVI, stroke volume index; and TPG, transpulmonary gradient.

^*Models for measures indexed to body surface area were not adjusted for BMI.

^† Primary variables.

In exploratory analyses adjusting for BSA in place of BMI, among individuals with HFpEF, women had higher RA pressure (β=0.30, SE=0.08, P=0.0001) but similar PAC (β=−0.19, SE=0.08, P=0.01) compared with men, findings that differed from the BMI‐adjusted results. Other findings were similar to BMI‐adjusted analyses.

Sex Differences in Hemodynamic Parameters in HFrEF

Among individuals with HFrEF, RV dysfunction (defined as PAPi <1.85) was similar among women compared with men (16% versus 19%, P=0.19). Similarly, In multivariable analyses adjusting for BMI and comorbidities, measures of RV function including RA/PCWP ratio, RVSWI, and PAPi did not differ between women and men (P>0.05 for all). However, women had higher Ea/RA pressure than men (β=0.35, SE=0.06, P<0.001). In terms of PV measures, women demonstrated higher PVR (β=0.32, SE=0.07), and lower PAC (β=−0.25, SE=0.07), compared with men (P<0.001 for both), with no observed sex differences in mean PA pressure. transpulmonary gradient was modestly elevated in women (β=0.12, SE=0.06, P=0.05) with borderline statistical significance. With respect to LV measures, women with HFrEF had significantly lower mean PCWP (β=−0.17, SE=0.07), CO (β=−0.36, SE=0.06), SV (β=−0.39, SE=0.06, P<0.05 for all) but similar CI and SVI (P>0.05 for both). Integrated measures of cardiac function showed that women had lower CPO (β=−0.21, SE=0.08, P=0.007), similar CPI (β=0.16, SE=0.08, P=0.049), and higher API (β=0.42, SE=0.09, P<0.001) compared with men. In exploratory analyses adjusting for BSA instead of BMI, female sex was associated with lower PAPi, although analyses did not meet the pre‐specified significance threshold. Associations with worse PVR and PAC were directionally consistent, although significance was attenuated. By contrast, sex differences in API remained significant.

DISCUSSION

In this study, we characterized sex differences in invasive hemodynamic measures among individuals with both HFpEF and HFrEF in a broad hospital‐based sample. We found that measures of RV function were similar among women and men regardless of HF subtype. By contrast, women with both HFpEF and HFrEF displayed worse PV function including higher PVR and lower PAC. This along with greater Ea/RAP suggests potentially more favorable RV adaptation in women versus men. Women also demonstrated worse LV measures, including lower CO and SV, although these differences were attenuated after indexing to BSA, with no significant sex differences in CI and SVI. Among integrated hemodynamic metrics, CPI was comparable between women and men, whereas API was higher in women, particularly among those with HFrEF. Overall, sex differences in hemodynamic measures were largely consistent across individuals with HFpEF and HFrEF.

Our finding that indices of RV function and RV dysfunction were similar among women and men with HF are consistent with other studies. For example, prior studies among individuals with HFpEF found that women and men have similar mean RA and RA/PCWP ratio, suggesting comparable degrees of congestion. ¹⁴ , ¹⁵ We additionally examined integrated hemodynamic indices of RV performance including RVSWI and PAPi, with the latter thought to be a better predictor of RV failure compared with RA/PCWP ratio or RVSWI among individuals with end‐stage HF undergoing LV assist device implantation. ¹⁶ Although fewer studies have examined sex differences in PAPi specifically within HF populations, findings from pulmonary hypertension cohorts have consistently demonstrated more favorable RV hemodynamic profiles among women compared with men. ¹⁷ In contrast to pulmonary arterial hypertension cohorts where younger, often premenopausal women exhibit superior RV function, our cohort was older, which may attenuate sex‐related differences observed in pulmonary arterial hypertension. It is also important to note that we find similar RV function in BMI‐adjusted analyses despite greater RV afterload in women, which reflect possibly more favorable RV adaptation in women versus men across both HF subtypes. These observations align with broader clinical and experimental evidence suggesting that women tend to exhibit better RV adaptation, possibly due to intrinsic biological differences. ¹⁸ , ¹⁹

In contrast to RV function measures, we found that women consistently exhibited worse measures of PV function compared with men. Our findings are consistent with other studies that have demonstrated that women with HFpEF exhibit lower PAC compared with men, both at rest and during exercise, reflecting greater PV stiffness. ¹ Importantly, these sex‐specific differences appear to be intrinsic and are not fully explained by differences in comorbidities or body size. Epidemiologic data further support this, showing that 82% of HFpEF patients with pulmonary hypertension are women, compared with 58% among those without pulmonary hypertension, suggesting a greater susceptibility of women to PV dysfunction. ²⁰ Our findings are consistent with these observations, showing that across HF subtypes, women had higher PVR, transpulmonary gradient, and lower PAC than men, indicating a reduced ability to accommodate increased pulmonary blood flow.

Regarding LV measures, women with HFpEF had similar resting PCWP compared with men in our study. This mirrors prior studies demonstrating similar PCWP among women and men across both health and disease. ¹ , ²¹ However, it is important to note that sex differences in PCWP among HFpEF patients may be unmasked during exercise, with women experiencing a steeper rise in PCWP during exercise compared with men. ¹ , ² By contrast, among individuals with HFrEF, we observed lower PCWP in women compared with men, though absolute differences were modest. We also found that women display lower CO and SV compared with men across HF subtypes; however, CI and SVI were similar between sexes, indicating that these differences were possibly driven by body size, consistent with prior studies. ¹ , ² , ²²

Recent studies have used CPO and CPI as integrated measures of overall cardiac pump performance and have demonstrated that higher CPO and CPI reflects better cardiac performance and improved survival in advanced HF and cardiogenic shock. ³ , ²³ Interestingly, we demonstrate that women with HF had lower CPO compared with men. However, after indexing to BSA, CPI was comparable between sexes. Our findings align with prior observations in ambulatory patients with advanced chronic HFrEF, where lower CPO among women was observed. ²³ This is notable since impaired recruitment of cardiac power reserve has been recognized as a fundamental physiological defect in HF across the EF spectrum. ²⁴ By contrast, API integrates LV pulsatility and filling pressures, with prior studies showing that lower API confers additional prognostic value including greater progression to advanced therapies or death compared with CO or PAPi among individuals with acute decompensated HFrEF. ⁴ , ¹¹ This finding may in part be due to known sex differences in arterial stiffness and left atrial compliance, with greater arterial elastance and stiffness among women versus men across health and disease. ² , ²⁵ Among individuals with HFpEF, sex differences in CPO and API were attenuated. This disparate pattern of lower CPO yet higher API in women compared with men with HFrEF may reflect generally smaller ventricular chamber size, greater arterial stiffness, and higher arterial elastance for a given blood pressure—factors that can elevate API, a load‐dependent index, while limiting SV and thereby reducing CPO. These observations underscore the need for future studies to elucidate the mechanistic basis of these differences and to inform sex‐specific strategies for risk stratification and therapy in HF.

Several limitations of our study should be acknowledged. The observational cross‐sectional design limits causal inferences. For example, it is unclear whether sex differences are inherent even in normal cardiovascular physiology, and persist among individuals with HF, or whether sex differences may causally and differentially predispose women versus men to particular HF subtype and development of HF. In addition we acknowledge that our findings may be subject to residual confounding including clinical characteristics that were not captured in our data and may differ by sex. Hemodynamic measurements were obtained at rest, which may not fully capture dynamic reserve or exercise intolerance, particularly relevant in HFpEF. Further, hemodynamic data were obtained from individuals undergoing clinically indicated RHC, most of whom were in a decompensated state, and it remains unclear whether patients were fully medically optimized at the time of assessment. Catheterizations followed standardized institutional protocols, though inter‐operator variability may have contributed to measurement variability. Moreover, our cohort was predominantly older, limiting the ability to evaluate sex‐related differences in younger or premenopausal individuals. Finally, we acknowledge that generalizability may be limited given that our sample was drawn from one single hospital‐based setting.

In sum, we delineated sex differences in invasive hemodynamic measures of RV, PV, and LV function among a hospital‐based sample of individuals with HFpEF and HFrEF undergoing RHC. We demonstrate similar measures of RV function among women versus men, whereas women exhibit worse PV and LV function. Notably, these findings were consistent among individuals with HFpEF and HFrEF. Finally, we examined emerging integrated metrics and demonstrated similar CPI, yet higher API among women versus men with HF, suggesting that future studies focused on clinical implications of these integrated hemodynamic measures among individuals with advanced HF should consider sex differences.

Sources of Funding

Dr Ho is supported by grants from the NIH (R01 HL140224, R01 HL160003, R01 HL168889, K24 HL153669). Dr Kosyakovsky is supported by NIH T32 HL160522. Dr Lau is supported by grants from the National Institutes of Health (K23‐HL159243), the Massachusetts Life Sciences Center, and the Tianqiao & Chrissy Chen Institute.

Disclosures

Dr Ho has received consulting fees from Eli Lilly. The remaining authors have no disclosures to report.

Supporting information

Tables S1–S2

STROBE checklist