There is growing interest in examining hemodynamic responses during exercise to understand limitations of functional capacity in older adults who complain of dyspnea. Invasive hemodynamic evaluation during exercise stress may reveal defects that may not be apparent at rest. An exaggerated pulmonary artery wedge pressure (PAWP) response during exercise may indicate abnormal diastolic function of the left atrium (LA) or ventricle (LV) (4). In the absence of structural heart disease, such a response may identify latent heart failure with preserved ejection fraction (HFpEF) (2,4) as a cause of dyspnea and exercise limitation. Recent investigations have revealed that the PAWP response to exercise is complex (19,30) and it may be important to interpret PAWP in context of exercise work rate (8). Our laboratory has demonstrated that in healthy subjects, the PAWP response is “time variant” and not fixed as submaximal exercise work rate is sustained (30). Thus, evaluating the pattern of PAWP in response to lighter work rates may be a useful method to assess patients with limited exercise tolerance.
This study addresses an ongoing knowledge deficit regarding the physiologic reference range of the PAWP response to exercise. Sex differences in LV chamber structure and function may predispose women to elevated LV and LA pressures during exercise (10,14), suggesting that PAWP response may be different in women compared with men based on more limited diastolic reserve. The objective of our study was to examine sexual dimorphism of the pattern of PAWP responses during exercise adjusted for work rate in healthy, nondyspneic older adults. This knowledge is essential to defining a normal reference range for diagnostic exercise testing, which then should be sex specific.
Healthy, physically untrained men and women ≥45 yr of age were recruited from the community. All participants underwent screening medical history, morphometric measurements, physical examination, 12-lead electrocardiogram, and an echocardiogram. Inclusion criteria composed of postmenopausal status in women, normal sinus rhythm, and QRS waveform duration <110 ms. Participants were excluded if they had a history of any cardiovascular disease or therapies, diabetes mellitus, or other chronic pulmonary, hepatic, renal, metabolic, systemic, neuromuscular, or malignant disease. Further exclusion criteria included body mass index >30 kg·m−2, blood pressure >140/90 mm Hg, >30 min of exercise per day more than three times per week, hormone replacement therapy, and significant LV hypertrophy or valvular abnormalities. All participants provided written, informed consent, and the study was approved by the Mount Sinai research ethics board (REB no. 11-0190-A).
Experimental procedures: cardiac catheterization
Right heart catheterization was performed at rest and during submaximal exercise, as previously reported (30,31). Briefly, a 7Fr multilumen balloon floatation pulmonary artery catheter (Swan-ganz Oximetry TD Catheter, Edwards Lifesciences) was advanced from a peripheral venous access under fluoroscopic guidance. Brachial blood pressure was measured intermittently with a noninvasive automated system (Tango+; SunTech Medical, Raleigh, NC) on the arm opposite of venous access.
After instrumentation, participants were transferred to a purpose-built cycle ergometer (Ergoselect 1200E; Ergoline, Windhagen, Germany), inclined to a semi-upright position, and pressure was acquired from the proximal (right atrial) and distal (pulmonary artery) catheter ports continuously for offline analysis (MacLab version 6.5, 300 Hz; GE Healthcare, Mississauga, ON, Canada). Continuous reflection spectrophotometry mixed venous oxygen saturation measurements were available. Hemodynamic measurements were determined in the following sequential conditions: baseline (supine rest); control (semi-upright rest); light exercise, at a work rate eliciting HR of 100 bpm for 8–10 min; and moderate exercise, at a work rate eliciting HR of 120 bpm for 8–10 min. Intermittent balloon inflation to measure PAWP was performed at 1 min. Before the onset of cycling at control, during light exercise at 2 min (early light) and 7 min (sustained light) after onset of cycling, and during moderate exercise at 2 min (early moderate) and 7 min after escalation of work rate (sustained moderate). Cardiac output (CO) was measured during the sustained phase of each exercise condition at 7 min, using the thermodilution technique, averaged from triplicate measurements with ≤10% variation.
Hemodynamics (right atrial, systolic/diastolic/mean pulmonary artery pressure [PAP], PAWP) were analyzed from digital recordings as previously reported (30). PAWP was reported by visual determination of mean PAWP at end expiration. Calculated variables are reported using end-expiratory PAWP. To describe the PAWP response to exercise, PAWP was adjusted to work rate (PAWR and PAWP/work rate, mm Hg·W−1) and adjusted as the ratio of PAWP to work rate normalized to body weight (PAWRwt and PAWP/[work rate/body weight], mm Hg·W−1·kg−1) and height (PAWRht and PAWP/[work rate/height], mm Hg·W−1·cm−1).
Normality of general characteristics and hemodynamic variables at baseline was assessed using the Shapiro–Wilk test. Data are presented as mean ± SD, or median (interquartile range) as appropriate. General characteristics and baseline hemodynamics were compared between men and women using Student's t-test or Mann–Whitney U-test. A general linear model was applied to explore the effect of sex on exercise hemodynamic variables, adjusted by age. Comparisons of continuous variables between exercise conditions and groups were performed using two-way repeated-measures ANOVA, assuming normal distribution. Significant main effects were analyzed post hoc using Bonferonni-adjusted t-tests. The relationships between CO and work rate and between PAWP and CO were assessed using simple linear regression. All statistical analyses were performed using SPSS Version 20 (IBM). A P value of <0.05 was considered significant.
Subject characteristics and baseline hemodynamics
Thirty-six subjects (18 men and 18 women) completed the study. Selected hemodynamic variables from 28 of these subjects (16 men and 12 women) were previously published by our group (30,31). Clinical and echocardiographic characteristics and resting hemodynamics are presented in Table 1. Women were slightly older than men. Height, weight, body surface area (BSA), and hemoglobin were all significantly greater in men compared with women. Body mass index was similar between the two groups. Two-dimensional echocardiographic-derived LV dimensions, LA diameter, and LA diameter index were significantly greater in men compared with women. LV mass was also significantly greater in men compared with women, even when indexed to BSA. Pulsed wave Doppler echocardiographic measures of LV diastolic function were similar between the sexes. Doppler-derived CO and SV were significantly lower in women compared with men but did not differ when indexed to BSA. LV geometry and function were within normal limits for both men and women. Compared with women, CO and SV were higher in men, indexed to BSA or height. There were slight differences in right atrial pressure and PAWP.
PAWP response to exercise
Exercise responses are shown in Tables 2 and 3. Work rates required to elicit the same target HR at light and moderate exercise were significantly lower in women. At both sustained light and sustained moderate exercise, CO and SV increased, although they remained significantly lower in women. Although systemic blood pressure demonstrated a stepwise increase throughout exercise, the pattern of PAWP responses differed. During each exercise stage, PAWP increased early, declining as exercise was sustained at steady intensity (Fig. 1A). Quantitatively, the absolute PAWP response was similar between sexes across both exercise intensities. PAWP increased significantly at early light exercise (22 ± 5 mm Hg in both groups) and then significantly decayed at sustained light exercise (17 ± 5 and 18 ± 5 mm Hg in men and women, respectively). After escalation of work rate, PAWP increased at early moderate exercise (20 ± 6 mm Hg) and then decreased during sustained moderate exercise (15 ± 5 mm Hg) in both groups.
In both men and women, PAWR was highest at the onset of exercise, related to the early increase in PAWP despite small work rate. PAWR then demonstrated a decline over the subsequent stages of the exercise protocol (Fig. 1B). The pattern of PAWRwt and PAWRht was very similar to PAWR (Fig. 1C and 1D). At all conditions, PAWR, PAWRwt, and PAWRht were significantly higher in women and changes between exercise conditions were significantly greater in women compared with men.
CO and work rate relationship
In both groups, increasing work rate was linearly related to CO (Fig. 2A). However, despite matching HR as a surrogate for matching effort, women demonstrated a narrower range of response for both work rate and CO.
PAWP to CO slope
The linear relationship between PAWP and CO slope over the two sustained stages of submaximal exercise was described by the equation PAWP = CO × 0.75 + 8.2 (Fig. 2B). However, expressing the change in PAWP per change in CO from control shows this quantity declines significantly between light and moderate exercise in both men and women (Fig. 3). Hence, at light exercise, the change in PAWP per change in CO was 1.2 ± 0.76 mm Hg·L−1·min−1 in men and 1.3 ± 0.88 mm Hg·L−1·min−1 in women and the range of this relationship was broad, with one woman demonstrating a value >3 mm Hg·L−1·min−1. At sustained moderate exercise, the slope of this relationship declined in both groups to 0.43 ± 0.40 mm Hg·L−1·min−1 in men and 0.45 ± 0.54 mm Hg·L−1·min−1 in women, with no volunteer exceeding 2 mm Hg·L−1·min−1.
In this prospective study, we examined the potential for sexual dimorphism of the PAWP response to submaximal exercise in healthy, nondyspneic older adults. In this population, we have reported that the relationships between PAP, PAWP, and CO are complex, with a broad range of response particularly to “slight” exercise early after exercise onset (30). The PAWP response is also time variant and declines when exercise is sustained. The absolute responses of PAWP during graded exercise were quantitatively similar between men and women. However, women demonstrated a relatively larger PAWP response after consideration of two important factors, exercise work rate and body size. PAWR, PAWRwt, and PAWRht exhibited apparent differences during exercise at lower work rate with large variation in response particularly in women; the sex differences persisted as exercise increased to moderate intensity over a period of minutes. Thus, PAWP for a given work rate was higher in women than men even as exercise was sustained.
The classic approach of expressing PAP and PAWP to flow or CO is fundamental to hemodynamic assessment, based on principles of hydraulic pumps. However, during exercise, there may be feasibility challenges in repeatedly measuring CO using an indicator dilution technique or using breath-by-breath gas-exchange analysis and deriving flow by Fick principles. The interpretation of exercise pressure responses relative to work rate alone is influenced by individual variability in exercise efficiency. In addition, there is variability in individuals' resting, maximal and rate of change in HR with a given exercise stimulus. Our intent in matching for HR was as a surrogate of matching effort. We did show that CO was linearly associated with work rate, supporting the use of PAWRwt as an alternative approach (8,19) to interpreting PAWP in context of presumed exercise-associated changes in CO (when measurement of CO is not possible) that is relatively simple to measure using an ergometer. In an earlier study, PAWRwt was found to be a more sensitive measure to detect abnormal hemodynamics in suspected HFpEF (19). In this study, we identified a pattern of an early peak PAWRwt with exercise onset and then a stepwise decline as exercise progressed to moderate intensity in both women and men. Rather than the vacillating behavior of PAWP, the decay pattern of PAWRwt may be a more useful metric by which to show that the PAWP response is time variant. At moderate intensity, values for PAWRwt were similar to that reported from a control population by Maeder et al. (19). The work of Dorfs et al. (8) highlighted the clinical significance of PAWRwt, demonstrating retrospectively that PAWRwt had important prognostic value and was independently associated with survival in a cohort of patients with dyspnea of unknown origin.
Our data demonstrate that there are sex differences in the quantitative relationships between work rate or CO achieved during exercise and the PAWP response. Although several lines of evidence indicate that sexual dimorphism exists in cardiovascular structure and function (6,9,14,21,22), there are few hemodynamic data arising from healthy men and women. Comparative data from control populations in the literature are primarily retrospective in design and derived from patients referred for assessment of dyspnea, which may not truly reflect health (1,2,4,18,23,26,27,29). The current study is novel with respect to the overall health of the participants. Although women were slightly older, the differences in the PAWR, PAWRwt, and PAWRht responses to exercise remained significant after adjustment for age. The adjustment for body size or cardiac chamber size to address sexual dimorphism is necessary but problematic, as it may introduce a systematic quantitative bias (7,15–17). However, when we expressed PAWP adjusted for work rate alone (i.e., PAWR), independently of either body weight or height, it remained significantly different between men and women.
We examined the relationship between PAWP and CO at two intensities of exercise. Although a rise and fall in PAWP was observed within each condition, a clear attenuation of a further rise in PAWP occurred between the sustained light and the sustained moderate exercise conditions, despite CO increasing to its highest value throughout the exercise challenge. Even as light exercise was sustained, the increase in PAWP relative to the increase in CO was broad and in some volunteers approached 3 mm Hg·L−1·min−1. As exercise was sustained at higher intensity and CO further increased, this relationship declined to values similar to the findings of Lewis et al. (18). Using a ramp protocol, this group demonstrated that the overall slope of the relationship between PAWP and CO was 1.1 mm Hg·L−1·min−1 in a control population. Our findings are also consistent with observations by Kovacs et al. (13), who reported that total pulmonary resistance or slope of the relationship between mean PAP and CO was steeper early after exercise onset compared with later in an exercise challenge in healthy subjects >50 yr.
The current study is relevant to the growing number of important investigations that have shown elevations of PAWP during exercise can be a marker of latent HFpEF (4,8). These studies have measured and reported PAWP during symptom-limited peak exercise. Borlaug et al. (4) initially reported on patients complaining of exertional limitation without abnormalities of either LV systolic function or levels of brain natriuretic peptide. A proportion of this cohort demonstrated exaggerated increases in PAWP during slight exercise. However, the complexity of the PAWP response warrants caution in single measures of PAWP at symptom-limited peak exercise. There are likely absolute thresholds over which a given PAWP response is clearly abnormal. However, our prospective studies reveal that an early rise in PAWP after exercise onset or increase in exercise intensity can be observed in healthy older adults. If the duration of an exercise challenge is short, a relatively large increase in PAWP may not be specific for HFpEF, overlapping with the broad range of PAWP responses observed during early exercise in healthy subjects. Similarly, both the change in PAWP relative to CO and PAWRwt showed the highest value and range early after exercise onset, particularly in women. We hypothesize that the decline of PAWP responses as exercise intensity is sustained may quantitatively reflect physiologic LV diastolic reserve, which functions to attenuate the rise in LV filling pressures as exertion-related CO increases. Therefore, accounting for exercise duration and observing the patterns of response from multiple measurements may be considerations in the design and interpretation of invasive exercise testing, as recommended by Lewis et al. (18).
The published experience shows a clear preponderance of women in the population referred for hemodynamic exercise testing to evaluate dyspnea of unknown origin (4,8,26,27). Several factors likely contribute to this observation. Aging-related exertional breathlessness is more common in women (11). Moreover, exercise hemodynamic testing has shown potential for early detection of HFpEF or pulmonary arterial hypertension, conditions with clear female predilection (3,25). The current study highlighted quantitative differences in the relationships between CO and PAWP and the exercise work rate achieved between men and women. It is premature to state that women are predisposed to LV diastolic dysfunction, which was not directly measured in this study, although we have previously demonstrated that women exhibit limited capacity for enhancement of early diastolic relaxation (28). Our study did not measure breathlessness, which is a complex symptom related to multiple mechanisms in addition to possible contributions of cardiac filling pressures (5,20,24). However, we did show that PAWP is higher in women than men at any given exercise intensity. Thus, there may be a hemodynamic threshold that induces the onset of dyspnea at lower exercise intensities in women compared with men, even after adjusting for size and amount of exercise performed. Our work also highlights the need to consider sex-specific comparisons when differentiating between normal and abnormal hemodynamic exercise responses.
Although matching for HR may approximate similar relative effort between individuals of equal fitness levels, we did not formally measure peak oxygen consumption by metabolic exercise testing in our subjects. Thus, differences in aerobic fitness between men and women in our cohort may have been a confounding factor.
The utility of hemodynamic exercise testing has yet to be fully embraced as standard clinical practice (12). This study provides insights into the patterns of hemodynamic response to submaximal exercise and contributes sex-specific data from which reference ranges, representative of untrained healthy older nondyspneic adults, may be developed.
This work was supported by the Heart and Stroke Foundation of Ontario grant-in-aid no. T7336, the generous donations of the Daniels family, and the Mecklinger and Posluns families.
All authors declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
Conflicts of interest: none.
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