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Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction (HFpEF). However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remains unknown.
Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure (PCWP) and mean pulmonary arterial pressure (MPAP) to volume loading with rapid saline infusion (100-200 ml/min). Hemodynamic responses to saline infusion in HFpEF (n=11) were then compared to healthy young (<50yrs) and older-aged (≥50yrs) subjects. In healthy subjects, PCWP increased from 10±2 to 16±3 mmHg after ~1L and to 20±3 mmHg after ~2L of saline infusion. Older women displayed a steeper increase in PCWP relative to volume infused (16±4mmHg·L−1·m2) than the other 3 groups (p≤0.019). Saline infusion resulted in a greater increase in MPAP relative to cardiac output in women compared to men, irrespective of age. Subjects with HFpEF exhibited a steeper increase in PCWP relative to infused volume (25±12 mmHg·L−1·m2) than healthy young and older subjects (p≤0.005).
Filling pressures rise significantly with volume loading, even in normal volunteers. Older women and patients with HFpEF exhibit the largest increases in PCWP and MPAP.
Intravenous volume infusion increases left ventricular (LV) end-diastolic volume and filling pressures1, 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 data2. Diagnostic guidelines recommend rapid volume challenge or exercise testing to distinguish patients with pulmonary arterial hypertension (PAH), who may experience modest increases in pulmonary capillary wedge pressure (PCWP), from those with HFpEF3. However, there are limited data on what represents a normal versus pathological response of PCWP to volume infusion4. Similarly, normative data on how pulmonary arterial pressures respond to increased blood flow and increased left sided filling pressures with saline infusion are lacking.
Healthy sedentary aging leads to cardiovascular stiffening, resulting in impairment of LV diastolic function (prolonged LV relaxation and decreased LV compliance) and vascular function5-8. In addition, there is sexual dimorphism in the LV geometric and functional changes with normal aging9. A greater decline in long-axis velocities, a prolonged time to peak apical rotation during diastole10 and increased LV stiffness using invasive11 and non-invasive techniques12 have been reported in healthy older women compared to 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 to younger subjects, especially in women.
Therefore, the purposes of this study were 1) to characterize the normal hemodynamic response to rapid saline infusion in healthy subjects, 2) to evaluate age- and sex-related differences in this response, and 3) to compare the changes in LV filling and mean pulmonary arterial pressure (MPAP) during saline infusion in healthy subjects to those in HFpEF patients.
Sixty healthy subjects (30m/30f, aged 21-77) 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 reported5. Eleven HFpEF patients (≥ 65 years) were prospectively enrolled as previously reported13. This study consists of two experiments; Experiment I was performed to evaluate the effects of age and sex on hemodynamic changes after rapid saline infusion in healthy subjects, while Experiment II was performed to evaluate hemodynamic changes after rapid saline infusion in HFpEF patients.
Sixty healthy sedentary subjects were stratified into 4 groups according to age and sex; young (<50 years) men (n=13); older (≥50 years) 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 post-exercise 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 (4m/7f) were enrolled as previously reported13. 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 hospitalization13. Hemodynamic responses to rapid saline infusion were evaluated in HFpEF patients and were compared to those in healthy young and older subjects in experiment I. As there were more females in the HFpEF group, healthy subjects were randomly selected to match this male-female ratio in experiment II, and were stratified into two groups; young (<50 years, 7m/13f) and older (≥50 years, 10m/17f) subjects. Diuretics and beta-blockers were withheld on the morning of the study in HFpEF patients and were continued as soon as the study was completed.
Protocols for experiment I and II are shown in Figure 1. A 6Fr 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 waveforms5,13. Baseline measurements of PCWP, MPAP, heart rate, and cardiac output were performed. Cardiac output was measured by a modification of the acetylene rebreathing method5,14. Stroke volume (SV) was determined by cardiac output divided by heart rate.
After acquiring baseline data, warm isotonic saline was infused through an 18-gauge intravenous cannula placed from the antecubital vein facilitated at the 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 of 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 two stages of rapid saline infusion as described below.
In experiment I, two stages of rapid saline infusion were performed (Figure 1). Immediately after 10-15 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 following 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 vs. 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 vs. 1.11 ± 0.18L), or between young and older women (0.87 ± 0.12 vs. 0.87 ± 0.14 L).
In experiment II, one 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 (ranged from 0.30 ~ 1.0L), 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 mmHg.
Cardiac MRI images were obtained using a 1.5-tesla Philips NT scanner to evaluate LV mass, volume and LV mass-volume ratio within 1 week of the catheterization15. LV end-diastolic volume (EDV) and mass were measured using a steady-state free precision imaging sequence as previous reported5,13. During cardiac catheterization, LV images were obtained by two-dimensional echocardiography at all loading conditions and were analyzed by use of modified Simpson’s method of disks.
As external constraints influence LV volumes and pressures16, LV end-diastolic transmural filling pressure (LVTMP) was calculated as PCWP − RAP17,18. The PCWP and SV data were used to construct Starling (SV index/PCWP) curves. LV stroke work (SW) index was calculated as (mean BP − PCWP) × SV index by the acetylene re-breathing method19. LV preload/SW relationships were constructed, and the slopes of the LV preload/SW relationship were used to assess global LV systolic function to assess global LV systolic function. Total peripheral resistance (TPR) index was calculated as (brachial mean BP − RAP) × 80 divided by cardiac index. Transpulmonary gradient (TPG) was calculated as MPAP − PCWP, and pulmonary vascular resistance (PVR) index was determined as TPG × 80 divided by cardiac index.
Baseline red blood cell volume and total blood volume were measured by the carbon monoxide rebreathing method only in healthy subjects20-22. Briefly, at baseline, blood was drawn to assess hematocrit and venous carboxyhemoglobin (%HbCO) levels. After a priming dose of 99% carbon monoxide administration, a second dose of carbon monoxide was administered. Blood samples were collected 10 minutes after each administration of carbon monoxide, and percent %HbCO was measured using a diode-array spectrophotometer. The typical error for blood volume by this method in our laboratory is <3 %21.
Statistical analyses were performed using commercially available software. Data were expressed as mean ± SD in tables and mean ± SE in figures. Baseline hemodynamic and pressure data were analyzed by one-way ANOVA or ANCOVA with post-hoc analysis and the Kruskal-Wallis test was used for non-normally distributed data. For data obtained during saline infusion, two-way repeated measures ANOVA with Tukey post hoc analysis was applied to determine 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 relations. The relationship between MPAP and cardiac index augmentation was used to evaluate MPAP response patterns to increased blood flow into the pulmonary vasculature during NS123. A p value <0.05 was considered significant.
LVEDV and mass were lower in older women compared to young and older men (Table 1). A modest inverse correlation was observed between baseline PCWP and age in men, but not in women (Supplemental Figure 1).
Red blood cell volume indexed to body mass was smaller in women than men. There were no differences in red blood cell volume or total blood volume by age within the same sex (Supplemental Figure 2). 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).
Heart rate and SV significantly increased after NS1, but not after NS2 in all 4 groups (Figure 2, Supplemental Table 1). Mean BP increased slightly after NS2 compared to baseline, resulting in decreases in TPR index in all 4 groups with saline infusion.
Global LV systolic function assessed by the slope of preload/SW relations appeared similar between groups (Supplemental Figure 3A). 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 (Supplemental Figure 3B).
Rapid saline infusion significantly increased average PCWP in healthy subjects from 10 ± 2 mmHg to 16 ± 3 (NS1) and 20 ± 3 mmHg (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 the rate ≥ 150 ml/min (Supplemental Table 2). A PCWP>15 mmHg, which has been previously proposed as a partition value for defining elevated LV filling pressures3, 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 to each of the other 3 groups, both by absolute infused volume or volume indexed to BSA, suggesting a lower diastolic reserve during rapid volume expansion in older women (Figure 3C,D). When the baseline PCWP and the amount of saline relative to the absolute total blood volume were used as covariates, one-way ANCOVA analysis 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 to older men (10 ± 2 vs. 7 ± 1 mmHg·L−1·m2, p<0.001). The increase in LVTMP in older women was not statistically different from those in other 3 groups (ANOVA p=0.157). As shown in Figurer 3C-D, the slope describing the increase in PCWP relative to saline infused increased markedly with age in women but not men (age*sex interaction effect p=0.01 in both figures).
In contrast to the modest increase in systemic arterial BP, there were significant increases in MPAP (~80 %) and TPG (~ 50 %) in all 4 groups (Figure 2, Supplemental Table 1). Although overall changes in PVR index were similar among the 4 groups, PVR index appeared to increase slightly only in young and older women (Supplemental Table 1).
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 towards a steeper slope of the MPAP/saline relation compared to 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).
HFpEF patients were heavier and had higher BP. LV mass index and the ratio of LV mass to EDV were significantly greater in HFpEF patients compared to healthy controls, suggesting concentric remodeling in HFpEF. In these stable outpatients with HFpEF, mean PCWP at supine rest was relatively controlled; nevertheless, mean PCWP, RAP, LVTMP were all significantly higher in HFpEF patients than 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 controls (Figure 1, Table 3). Similar to healthy subjects, saline infusion increased SV index, MPAP, PCWP, and RAP in HFpEF. After NS1, a slight increase or no change in RAP with inspiration (Kussmaul’s sign) was observed in >60 % of the HFpEF patients and healthy controls, suggesting increased pericardial constraint. No HFpEF patients developed overt symptoms of heart failure during or after saline infusion.
As shown in Figure 5, the slope of the PCWP/saline relation was steeper in HFpEF than healthy young and older subjects. When analyzed individually, HFpEF patients exhibited a steeper PCWP/saline slope (25 ± 12 mmHg·L−1·m2) than young and older subjects (12 ± 3 and 14 ± 5 mmHg·L−1·m2, p≤0.005). When the baseline PCWP was used as a covariate, one-way ANCOVA analysis still exhibited a steeper PCWP/saline slope in HFpEF than young and older subjects (p< 0.001).
As compared to healthy young and older subjects, HFpEF patients also had steeper RAP/saline slope (13 ± 3 vs. 8 ± 2 and 9 ± 2 mmHg·L−1·m2, p<0.001) and LVTMP/saline slope (12 ± 10 vs. 4 ± 3 and 5 ± 4 mmHg·L−1·m2, p≤0.085). The RAP/saline slopes were significantly correlated to the PCWP/saline slopes in HFpEF patients, healthy young and older subjects (R2=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).
We demonstrate for the first time in healthy humans that rapid saline infusion increases filling pressures more in older women compared to men and younger women. Over 90% of normal volunteers were found to display increases in PCWP to values previously considered to define HFpEF (>15 mmHg) with ~2L of saline3,24. 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.
In animals, increases in LV end-diastolic pressure and volume after rapid volume challenge have been reported1,25. To our knowledge, there is one study which evaluated PCWP changes during saline infusion in healthy humans4. Contrary to our results, Kumar et al. observed only a modest increase in PCWP after infusion at the rate of 1 L/hour4. With such a slow rate, fluid is more likely to move from the central circulation to interstitial spaces26 or be redistributed into the venous capacitance vessels27, resulting in a blunted PCWP increase.
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 compliance16,29. In this study, Kussmaul’s sign was observed in >60% of the controls and HFpEF patients. In most cases, the PCWP demonstrated greater A and V waves with no prominent y-descent, consistent with coupled pericardial constraint30. In older women, a greater increase in RAP was observed during infusion, while 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 diabetes31. Therefore, our findings may partly explain this age and sex predilection in the HFpEF population.
Greater PCWP/saline slopes were observed in HFpEF compared to healthy subjects. These findings indicate that HFpEF patients had increased LV stiffening and/or the ventricles were operating on the steeper portion of their pressure-volume relations during saline infusion. RAP is mainly regulated by pericardial constraint17. 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 controls (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 pressure29. Thus, nitroglycerin might be a reasonable therapeutic option in HFpEF patients with high levels of pericardial constraint.
Total body blood volume can be stratified into the volumes in the arterial and nonsplanchnic systemic venous beds32. The largest absolute plasma and total blood volumes were observed in older men, while older men tended to have lower cardiac filling pressures compared to young men. We speculate that older men may have possessed a larger venous reservoir and/or smaller effective circulatory volume than other groups.
Volume challenge and exercise testing with right heart catheterization have been used to unmask diastolic dysfunction and diagnose HFpEF3,24,33. 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 current 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 exercise23,34. We also observed that healthy women have a smaller reserve for flow-mediated PA dilatation compared to men, which may predispose them to greater risk for pulmonary vascular disease with chronic left heart disease35,36.
First, the number of our HFpEF patients was small, and the control group was free of any cardiovascular diseases. The power of PCWP/saline slope analysis was 0.84 in experiment I and 0.70 in experiment II. Future studies are required to assess how effectively saline loading differentiates 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 hemodyanmics including PCWP during saline infusion at the rate<150 ml/min were quite similar to those at the rate≥150 ml/min in young women (Supplemental Table 2). 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 controls. 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 controls and between controls and HFpEF patients. Lastly, there were differences in age between HFpEF and healthy older subjects, and in body size among groups, which might have affected our results.
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” based upon 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 to men and to younger controls.
Funding Sources: This study was supported by the National Institutes of Health grant AG17479.
Conflict of Interest Disclosures: None.
Journal Subject Codes:  Congestive;  Pulmonary circulation and disease;  Other diagnostic testing
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