Hemodynamic Responses to Rapid Saline LoadingClinical Perspective
=================================================================

* Naoki Fujimoto
* Barry A. Borlaug
* Gregory D. Lewis
* Jeffrey L. Hastings
* Keri M. Shafer
* Paul S. Bhella
* Graeme Carrick-Ranson
* Benjamin D. Levine

## The Impact of Age, Sex, and Heart Failure

## Abstract

**Background—**Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown.

**Methods and Results—**Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L−1·m2) than the other 3 groups (*P*≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L−1·m2) than healthy young and older subjects (*P*≤0.005).

**Conclusions—**Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.

*   age and sex difference
*   filling pressure
*   heart failure
*   stroke volume
*   volume loading

## Introduction

Intravenous volume infusion increases left ventricular (LV) end-diastolic volume and filling pressures,1 which may be used diagnostically in certain patient populations. Heart failure with preserved ejection fraction (HFpEF) is often observed in elderly women with increased LV stiffening and/or prolonged relaxation but may be challenging to diagnose, even with invasive hemodynamic data.2 Diagnostic guidelines recommend rapid volume challenge or exercise testing to distinguish patients with pulmonary arterial hypertension, who may experience modest increases in pulmonary capillary wedge pressure (PCWP), from those with HFpEF.3 However, there are limited data on what represents a normal versus pathological response of PCWP to volume infusion.4 Similarly, normative data on how pulmonary arterial pressures respond to increased blood flow and increased left-side filling pressures with saline infusion are lacking.

**Clinical Perspective on p 62**

Healthy sedentary aging leads to cardiovascular stiffening, resulting in impairment of LV diastolic function (prolonged LV relaxation and decreased LV compliance) and vascular function.5–8 In addition, there is sexual dimorphism in the LV geometric and functional changes with normal aging.9 A greater decline in long-axis velocities, a prolonged time to peak apical rotation during diastole,10 and increased LV stiffness through the use of invasive11 and noninvasive techniques12 have been reported in healthy older women compared with men, suggesting that women are more likely to experience a reduction in LV diastolic function with age. Therefore, we speculate that these age- and sex-related changes in LV diastolic function may contribute to a greater increase in LV filling pressure during rapid saline infusion in older subjects compared with younger subjects, especially in women.

Therefore, the purposes of this study were to characterize the normal hemodynamic response to rapid saline infusion in healthy subjects, to evaluate age- and sex-related differences in this response, and to compare the changes in LV filling and mean pulmonary arterial pressure (MPAP) during saline infusion in healthy subjects with those in HFpEF patients.

## Methods

Sixty healthy subjects (30 men, 30 women; age, 21–77 years) were prospectively enrolled from the Dallas Heart Study, a population-based probability sample of individuals in the Dallas community or a second random sample of employees of Texas Health Resources as previously reported.5 Eleven HFpEF patients (≥65 years of age) were prospectively enrolled as previously reported.13 This study consists of 2 experiments. Experiment 1 was performed to evaluate the effects of age and sex on hemodynamic changes after rapid saline infusion in healthy subjects; experiment 2 was performed to evaluate hemodynamic changes after rapid saline infusion in HFpEF patients.

### Study Subjects

Sixty healthy sedentary subjects were stratified into 4 groups according to age and sex: young (<50 years of age) men (n=13), older (≥50 years of age) men (n=17), young women (n=13), and older women (n=17). Subjects were excluded if they were exercising for ≥30 minutes >2 times per week. All subjects were rigorously screened for comorbidities, including obesity, lung disease, hypertension, LV wall thickness ≥12 mm, coronary artery disease, or structural heart disease at baseline and by postexercise transthoracic echocardiograms. All subjects signed an informed consent form, which was approved by the institutional review boards of the University of Texas Southwestern Medical Center at Dallas and Texas Health Presbyterian Hospital Dallas.

Eleven rigorously screened HFpEF patients (4 men, 7 women) were enrolled as previously reported.13 HFpEF patients were defined as having a clear history of HF by Framingham criteria plus confirmatory evidence of pulmonary congestion by chest radiography, biomarker elevation, or catheterization, plus an ejection fraction >50% at the time of their index hospitalization.13 Hemodynamic responses to rapid saline infusion were evaluated in HFpEF patients and were compared with those in healthy young and older subjects in experiment 1. Because there were more women in the HFpEF group, healthy subjects were randomly selected to match this male/female ratio in experiment 2 and were stratified into 2 groups: young (<50 years of age; 7 men, 13 women) and older (≥50 years of age; 10 men, 17 women) subjects. Diuretics and β-blockers were withheld on the morning of the study in HFpEF patients and were continued as soon as the study was completed.

### Experimental Protocol

Protocols for experiments 1 and 2 are shown in Figure 1. A 6F Swan-Ganz catheter was placed from an antecubital vein under fluoroscopic guidance to measure PCWP, MPAP, and right atrial pressure (RAP).13 Correct position of the Swan-Ganz catheter was confirmed by fluoroscopy and by the presence of characteristic pressure waveforms.5,13 Baseline measurements of PCWP, MPAP, heart rate, and cardiac output were performed. Cardiac output was measured by a modification of the acetylene rebreathing method.5,14 Stroke volume (SV) was determined by cardiac output divided by heart rate.

![Figure 1.](http://circ.ahajournals.org/http://circ.ahajournals.org/content/circulationaha/127/1/55/F1.medium.gif)

[Figure 1.](http://circ.ahajournals.org/content/127/1/55/F1)

Figure 1. 
Protocols for experiments 1 and 2. HFpEF indicates heart failure with preserved ejection fraction; MPAP, mean pulmonary arterial pressure; NS1 and NS2, first and second sets of saline infusions; PCWP, pulmonary capillary wedge pressure; and RAP, right atrial pressure.

After baseline data were acquired, warm isotonic saline was infused through an 18-gauge intravenous cannula placed from the antecubital vein facilitated at a rate of ~200 mL/min by the use a pneumatic sleeve compressing the infusate. In some cases, a 20-gauge cannula from antecubital or peripheral vein was used when an 18-gauge cannula could not be placed, resulting in a slightly slower rate of infusion (100–150 mL/min). Heart rate, MPAP, and RAP were recorded continuously during saline infusion. Hemodynamic measurements were repeated after each of the 2 stages of rapid saline infusion as described below.

### Saline Infusion Protocol

In experiment 1, 2 stages of rapid saline infusion were performed (Figure 1). Immediately after 10 to 15 mL/kg of warm isotonic saline (NS1) was infused, PCWP and MPAP were recorded, followed by measurements of cardiac output within 2 minutes. Saline infusion was continued at ~10 mL/min after the first rapid infusion period (NS1) to maintain cardiac filling pressures at steady levels during NS1 measurements. Then, a second dose of saline was infused at the same rate (NS2), followed by repeat hemodynamic measurements. For ease of data comparison, the volume of saline indexed to body mass during NS1 was matched in men and women (13.7±1.6 versus 13.6±1.5 mL/kg). The absolute volume of saline infused during NS1 was similar between young and older men (1.10±0.16 and 1.11±0.18 L) or between young and older women (0.87±0.12 and 0.87±0.14 L).

In experiment 2, 1 stage of saline infusion was performed at a similar rate, followed by hemodynamic measurements (Figure 1). In HFpEF patients, the volume of infused saline was 0.55±0.23 L (range, 0.30–1.0 L), which was smaller for safety reasons than those in young (0.95±0.17 L) and older (0.97±0.20 L) subjects. The volume of saline per body mass in HFpEF was 6.1±1.9 mL/kg, and in all subjects, the infusion was stopped if pulmonary arterial diastolic pressure reached ≥25 mm Hg.

### Assessment of LV Morphology

Cardiac magnetic resonance images were obtained with a 1.5-T Philips NT scanner to evaluate LV mass, volume, and ratio of LV mass to volume within 1 week of the catheterization.15 LV end-diastolic volume and mass were measured with a steady-state free precision imaging sequence as previous reported.5,13 During cardiac catheterization, LV images were obtained by 2-dimensional echocardiography at all loading conditions and were analyzed by use of the modified Simpson method of disks.

### Cardiac Catheterization Data

Because external constraints influence LV volumes and pressures,16 LV end-diastolic transmural filling pressure (LVTMP) was calculated as PCWP minus RAP.17,18 The PCWP and SV data were used to construct Starling (SV index/PCWP) curves. LV stroke work index was calculated as follows: (mean BP−PCWP)×SV index, where BP is blood pressure, by the acetylene rebreathing method.19 LV preload/stroke work relationships were constructed, and the slopes of the LV preload/stroke work relationship were used to assess global LV systolic function. Total peripheral resistance index was calculated as follows: (brachial mean BP−RAP)×80/CI, where CI is cardiac index. Transpulmonary gradient was calculated as MPAP minus PCWP, and pulmonary vascular resistance index was determined as transpulmonary gradient times 80 divided by cardiac index.

### Measurements of Blood Volume

Baseline red blood cell volume and total blood volume were measured by the carbon monoxide rebreathing method only in healthy subjects.20–22 Briefly, at baseline, blood was drawn to assess hematocrit and venous carboxyhemoglobin levels. After administration of a priming dose of 99% carbon monoxide, a second dose of carbon monoxide was administered. Blood samples were collected 10 minutes after each administration of carbon monoxide, and percent venous carboxyhemoglobin was measured with a diode-array spectrophotometer. The typical error for blood volume by this method in our laboratory is <3%.21

### Statistical Analysis

Statistical analyses were performed with commercially available software. Data are expressed as mean±SD in tables and as mean±SE in figures. Baseline hemodynamic and pressure data were analyzed by 1-way ANOVA or ANCOVA with post hoc analysis, and the Kruskal-Wallis test was used for nonnormally distributed data. For data obtained during saline infusion, 2-way repeated measures ANOVA with Tukey post hoc analysis was applied to determine the main effects for group, loading condition, and interaction and to evaluate the differences between groups. A linear regression analysis was used to evaluate the relations between age and hemodynamic variables.

Changes in PCWP, RAP, LVTMP, and MPAP relative to infused saline during NS1 were assessed by the slopes of PCWP/saline, RAP/saline, LVTMP/saline, and MPAP/saline relationships. The relationship between MPAP and cardiac index augmentation was used to evaluate MPAP response patterns to increased blood flow into the pulmonary vasculature during NS1.23 A value of *P*<0.05 was considered significant.

## Results

### Experiment 1

#### Ventricular Structure and Hemodynamics at Rest

LV end-diastolic volume and mass were lower in older women compared with young and older men (Table 1). A modest inverse correlation was observed between baseline PCWP and age in men but not in women (Figure I in the online-only Data Supplement).

View this table:
[Table 1.](http://circ.ahajournals.org/content/127/1/55/T1)

Table 1. 
Subjects’ Characteristics: Experiment 1

#### Blood Volume Measurements

Red blood cell volume indexed to body mass was smaller in women than in men. There were no differences in red blood cell volume or total blood volume by age within the same sex (Figure II in the online-only Data Supplement). The amounts of saline infused during NS1 relative to the total blood volume in young men, older men, young women, and older women were 0.21±0.03, 0.20±0.03, 0.22±0.02, and 0.22±0.02, respectively (ANOVA *P*=0.090).

#### Hemodynamic Responses to Saline Infusion in Healthy Subjects

Heart rate and SV significantly increased after NS1 but not after NS2 in all 4 groups (Figure 2 and Table I in the online-only Data Supplement). Mean BP increased slightly after NS2 compared with baseline, resulting in decreases in total peripheral resistance index in all 4 groups with saline infusion.

![Figure 2.](http://circ.ahajournals.org/http://circ.ahajournals.org/content/circulationaha/127/1/55/F2.medium.gif)

[Figure 2.](http://circ.ahajournals.org/content/127/1/55/F2)

Figure 2. 
Changes in heart rate, stroke volume (SV) index, mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and left ventricular end-diastolic transmural filling pressure (LVTMP) during rapid saline infusion. Two-way repeated measures ANOVA with post hoc analysis was used. NS1 and NS2 indicate first and second sets of saline infusions. • Indicates young men; ○, older men; ▴, young women; and Δ, older women. **P*<0.05 vs older men, †*P*<0.05 vs young men, and ‡*P*<0.05 vs older women within the same loading condition.

Global LV systolic function assessed by the slope of preload/stroke work relations appeared to be similar between groups (Figure IIIA in the online-only Data Supplement). The Starling curves in young and older men showed a larger SV index at any given PCWP than those in young women during saline infusion (Figure IIIB in the online-only Data Supplement).

Rapid saline infusion significantly increased average PCWP in healthy subjects from 10±2 to 16±3 mm Hg (NS1) and 20±3 mm Hg (NS2; *P*<0.001; Figure 2). A slower rate of saline infusion (100–150 mL/min) in young women resulted in an increase in PCWP similar to that after saline infusion at a rate ≥150 mL/min (Table II in the online-only Data Supplement). A PCWP >15 mm Hg, which has previously been proposed as a partition value for defining elevated LV filling pressures,3 was observed in 62% of the healthy subjects after NS1 and 93% of the subjects after NS2.

As shown in Figure 3, the increase in PCWP for any volume of saline infused was greater in older women compared with each of the other 3 groups by both absolute infused volume and volume indexed to body surface area, suggesting a lower diastolic reserve during rapid volume expansion in older women (Figure 3C and 3D). When the baseline PCWP and the amount of saline relative to the absolute total blood volume were used as covariates, 1-way ANCOVA still showed a steeper PCWP/saline slope in older women than the other 3 groups (*P*≤0.01). A greater increase in RAP relative to saline was also observed in older women compared with older men (10±2 versus 7±1 mm Hg·L−1·m2; *P*<0.001). The increase in LVTMP in older women was not statistically different from those in the other 3 groups (ANOVA *P*=0.157). As shown in Figure 3C and 3D, the slope describing the increase in PCWP relative to saline infused increased markedly with age in women but not men (age-by-sex interaction effect, *P*=0.01 in Figure 3C and 3D).

![Figure 3.](http://circ.ahajournals.org/http://circ.ahajournals.org/content/circulationaha/127/1/55/F3.medium.gif)

[Figure 3.](http://circ.ahajournals.org/content/127/1/55/F3)

Figure 3. 
**A** and **B**, Pulmonary capillary wedge pressure (PCWP) relative to saline after the first set of saline infusions (NS1; top left) and the relationship between PCWP/saline slope and age (top right). **C** and **D**, PCWP relative to saline after NS1 (bottom left) and the relationship between PCWP/saline slope and age in healthy subjects (bottom right). The graphs on the bottom display indexed values. • Indicates young men; ○, older men; ▴, young women; and Δ, older women. **P*<0.05 vs older women.

In contrast to the modest increase in systemic arterial BP, there were significant increases in MPAP (~80%) and transpulmonary gradient (~50%) in all 4 groups (Figure 2 and Table I in the online-only Data Supplement). Although overall changes in pulmonary vascular resistance index were similar among the 4 groups, pulmonary vascular resistance index appeared to increase slightly in only young and older women (Table I in the online-only Data Supplement).

The MPAP/saline relation in older women was significantly steeper than slopes observed in young and older men (Figure 4A). Young women also had a tendency toward a steeper slope of the MPAP/saline relation compared with men. There were significant sex disparities in the increase in MPAP relative to cardiac index (ANOVA *P*≤0.018; Figure 4B). Women had greater MPAP/cardiac index slopes than men (*P*≤0.065), but within the sexes, there was no age-related differences in MAP/cardiac index slopes (*P*>0.50 for men and women).

![Figure 4.](http://circ.ahajournals.org/http://circ.ahajournals.org/content/circulationaha/127/1/55/F4.medium.gif)

[Figure 4.](http://circ.ahajournals.org/content/127/1/55/F4)

Figure 4. 
**A**, Mean pulmonary arterial pressure (MPAP) relative to saline after the first set of saline infusions (NS1) in healthy subjects (left). • Indicates young men; ○, older men; ▴, young women; and Δ, older women. **P*<0.05 vs older women. **B**, MPAP relative to cardiac index after NS1. **P*<0.05 vs older women; †*P*<0.05 vs young women.

### Experiment 2

HFpEF patients were heavier and had higher BP. LV mass index and the ratio of LV mass to end-diastolic volume were significantly greater in HFpEF patients compared with healthy control subjects, suggesting concentric remodeling in HFpEF. In these stable outpatients with HFpEF, mean PCWP at supine rest was relatively controlled; nevertheless, mean PCWP, RAP, and LVTMP were all significantly higher in HFpEF patients than in young and older subjects (Table 2). Because of the risk of precipitating heart failure decompensation, the total and body size–normalized volume of saline administered was lower in HFpEF than in control subjects (Figure 1 and Table 3). Similar to healthy subjects, saline infusion increased SV index, MPAP, PCWP, and RAP in HFpEF patients. After NS1, a slight increase or no change in RAP with inspiration (Kussmaul sign) was observed in >60% of the HFpEF patients and healthy control subjects, suggesting increased pericardial constraint. No HFpEF patients developed overt symptoms of heart failure during or after saline infusion.

View this table:
[Table 2.](http://circ.ahajournals.org/content/127/1/55/T2)

Table 2. 
Subjects’ Characteristics: Experiment 2

View this table:
[Table 3.](http://circ.ahajournals.org/content/127/1/55/T3)

Table 3. 
Hemodynamic Responses to Saline Infusion: Experiment 2

As shown in Figure 5, the slope of the PCWP/saline relation was steeper in HFpEF than in healthy young and older subjects. When analyzed individually, HFpEF patients exhibited a steeper PCWP/saline slope (25±12 mm Hg·L−1·m2) than young and older subjects (12±3 and 14±5 mm Hg·L−1·m2; *P*≤0.005). When the baseline PCWP was used as a covariate, 1-way ANCOVA still exhibited a steeper PCWP/saline slope in HFpEF than young and older subjects (*P*<0.001).

![Figure 5.](http://circ.ahajournals.org/http://circ.ahajournals.org/content/circulationaha/127/1/55/F5.medium.gif)

[Figure 5.](http://circ.ahajournals.org/content/127/1/55/F5)

Figure 5. 
Pulmonary capillary wedge pressure (PCWP) relative to saline in patients with heart failure with preserved ejection fraction (HFpEF), young subjects, and older subjects after the first set of saline infusions (NS1). Dashed line indicates 95% confidence limits; •, young subjects; ○, older subjects; and ▪, HFpEF patients. **P*<0.05 vs HFpEF patients.

Compared with healthy young and older subjects, HFpEF patients also had steeper RAP/saline slope (13±3 versus 8±2 and 9±2 mm Hg·L−1·m2; *P*<0.001) and LVTMP/saline slope (12±10 versus 4±3 and 5±4 mm Hg·L−1·m2; *P*≤0.085). The RAP/saline slopes were significantly correlated to the PCWP/saline slopes in HFpEF patients, healthy young subjects, and older subjects (*R*2=0.466, 0.211, and 0.379; *P*≤0.041). No difference was observed in PAP/saline slope among the 3 groups (ANOVA *P*=0.137).

## Discussion

We demonstrate for the first time in healthy humans that rapid saline infusion increases filling pressures more in older women compared with men and younger women. More than 90% of normal volunteers were found to display increases in PCWP to values previously considered to define HFpEF (>15 mm Hg) with ~2 L saline.3,24 In addition, the greatest increase in PCWP with saline infusion was noted in HFpEF, consistent with impaired diastolic reserve. Finally, the lower diastolic volume loading reserve observed in older women offers novel insight into the greater predilection for older-aged women to develop HFpEF.

### PCWP Responses to Rapid Saline Infusion in Healthy Subjects

In animals, increases in LV end-diastolic pressure and volume after rapid volume challenge have been reported.1,25 To the best of our knowledge, 1 study has evaluated PCWP changes during saline infusion in healthy humans.4 Contrary to our results, Kumar et al4 observed only a modest increase in PCWP after infusion at a rate of 1 L/h. With such a slow rate, fluid is more likely to move from the central circulation to interstitial spaces26 or to be redistributed into the venous capacitance vessels,27 resulting in a blunted PCWP increase.

### Effects of Age and Sex on PCWP During Rapid Saline Infusion

Age increased the gain in filling pressures with saline infusion in older women. Volume loading shifts the operating point on the curvilinear LV end-diastolic pressure-volume relation to a steeper position28; thus, the absolute increase in PCWP relative to saline infusion could be accentuated in subjects with steep end-diastolic pressure-volume relations. Pericardial constraint significantly elevates LV filling pressure and influences LV chamber compliance.16,29 In this study, the Kussmaul sign was observed in >60% of the control subjects and HFpEF patients. In most cases, the PCWP demonstrated greater A and V waves with no prominent y descent, consistent with coupled pericardial constraint.30 In older women, a greater increase in RAP was observed during infusion, whereas the increase in LVTMP was not different from those in other groups. These findings may suggest that LV hemodynamics in older women are more affected by pericardial constraint. HFpEF patients are more likely to be older women with hypertension and diabetes mellitus.31 Therefore, our findings may partly explain this age and sex predilection in the HFpEF population.

### Saline Loading Responses in HFpEF

Greater PCWP/saline slopes were observed in HFpEF patients compared with healthy subjects. These findings indicate that HFpEF patients had increased LV stiffening and/or that the ventricles were operating on the steeper portion of their pressure-volume relations during saline infusion. RAP is regulated mainly by pericardial constraint.17 Thus, a greater RAP/saline slope in HFpEF may indicate that HFpEF patients are more affected by pericardial constraint than healthy older subjects. We also point out that LVTMP/saline slopes appeared to be greater in HFpEF patients than healthy control subjects (*P*≤0.085). These findings suggest that it is not exclusively the pericardium that causes the rise in filling pressures during saline infusion. Venodilation with nitroglycerin reduces pericardial constraint and lowers cardiac filling pressure.29 Thus, nitroglycerin might be a reasonable therapeutic option in HFpEF patients with high levels of pericardial constraint.

### Blood Volume/Plasma Volume Data

Total body blood volume can be stratified into the unstressed and stressed volumes in the arterial and nonsplanchnic systemic venous beds.32 The largest absolute plasma and total blood volumes were observed in older men, whereas older men tended to have lower cardiac filling pressures compared with young men. We speculate that older men may have possessed a larger venous reservoir and/or smaller effective circulatory volume than other groups.

### Invasive Hemodynamic Stress Testing

Volume challenge and exercise testing with right heart catheterization have been used to unmask diastolic dysfunction and to diagnose HFpEF.3,24,33 In contrast to exercise testing, saline loading has minor effects on BP and HR and predominantly tests operant diastolic ventricular compliance. Saline infusion is more widely available than invasive exercise testing, and the present data may expand the capability to perform provocative invasive assessment to more laboratories. Intriguingly, we observed that rapid saline infusion had greater effects on the pulmonary circulation than previously reported during exercise.23,34 We also observed that healthy women have a smaller reserve for flow-mediated pulmonary artery dilatation compared with men, which may predispose them to greater risk for pulmonary vascular disease with chronic left heart disease.35,36

### Study Limitations

First, the number of our HFpEF patients was small, and the control group was free of any cardiovascular diseases. The power of the PCWP/saline slope analysis was 0.84 in experiment 1 and 0.70 in experiment 2. Future studies are required to assess how effectively saline loading differentiates patients with HFpEF from patients with other cardiovascular diseases such as systemic and pulmonary arterial hypertension. Second, saline was not infused at precisely the same rate in all subjects because of the inability to obtain large-bore cannulas. However, most catheterization laboratories do not have the capability to precisely regulate infusion rates. Moreover, the changes in hemodynamics, including PCWP, during saline infusion at a rate <150 mL/min were quite similar to those at a rate ≥150 mL/min in young women (Table II in the online-only Data Supplement). We believe that this range is relevant to clinical practice. Third, the total but not scaled volume of infused saline was lower in women than men and in HFpEF patients than control subjects. It is possible but unlikely that the initial increment in filling pressures was greater than increments with more volume because responses of filling pressures to rapid infusion were approximately linear (Figure 2). Fourth, blood volume was not measured in HFpEF patients. Differences in the preinfusion distribution of blood volume or the distribution of the infused saline within the systemic veins and regional venous capacitance vessels might have contributed to the observed differences within control subjects and between control subjects and HFpEF patients. Finally, there were differences in age between HFpEF and healthy older subjects and in body size among groups, which might have affected our results.

### Conclusions

In healthy humans rigorously screened for cardiovascular disease, there are significant elevations in left and right heart filling pressures during rapid saline infusion, suggesting that currently proposed partition values of PCWP used to define “heart failure” from saline loading need to be revisited. The increase in PCWP during saline infusion was greatest in older women, suggesting more loss of diastolic and pericardial compliance reserve in the aged female heart compared with men and to younger control subjects.

## Source of Funding

This study was supported by National Institutes of Health grant AG17479.

## Disclosures

None.

## Footnotes

*   The online-only Data Supplement is available with this article at [http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.112.111302/-/DC1](http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.112.111302/-/DC1).

*   Received April 26, 2012.
*   Accepted November 7, 2012.


*   © 2013 American Heart Association, Inc.

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# Clinical Perspective {#article-title-38}

A volume challenge unmasks left ventricular diastolic dysfunction and therefore has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. In the present study, we assessed age- and sex-related normative responses of pulmonary capillary wedge pressure to rapid saline infusion (100–200 mL/min) in 60 healthy subjects. Hemodynamic responses to saline infusion in 11 patients with heart failure with preserved ejection fraction were then compared with those in healthy young and older subjects. Rapid saline infusion significantly increased pulmonary capillary wedge pressure from 10±2 to 16±3 mm Hg with ~1 L saline and to 20±3 mm Hg with ~2 L saline in healthy subjects. More than 90% of the healthy subjects exhibited pulmonary capillary wedge pressure values previously considered to define heart failure with preserved ejection fraction (>15 mm Hg) with ~2 L saline. In older women, a greater increase in pulmonary capillary wedge pressure relative to volume infused was observed compared with men and younger women, suggesting more dramatic loss of diastolic reserve in older women. The greatest increase in pulmonary capillary wedge pressure relative to volume infused was noted in patients with heart failure with preserved ejection fraction, consistent with the most severely impaired diastolic reserve. These data could constitute an important step for the development of diagnostic protocols for the invasive evaluation of patients with dyspnea. Future studies will assess how effectively saline loading differentiates patients with heart failure with preserved ejection fraction from patients with other cardiovascular diseases such as systemic and pulmonary arterial hypertension.