Abstract
In healthy subjects the arterial system and the left ventricle (LV) are tightly coupled at rest to optimize cardiac performance. Systolic hypertension (SH) is a major risk factor for heart failure and is associated with structural and functional alterations in the arteries and the LV. The effects of SH and resting systolic blood pressure (SBP) on arterial-ventricular coupling (EaI/ELVI) at rest, at peak exercise, and during recovery are not well described. We noninvasively characterized EaI/ELVI as end-systolic volume index/stroke volume index in subjects who were normotensive (NT, n = 203) or had SH (brachial SBP ≥140 mmHg, n = 79). Cardiac volumes were measured at rest and throughout exhaustive upright cycle exercise with gated blood pool scans. EaI/ELVI reserve was calculated by subtracting peak from resting EaI/ELVI. At rest, EaI/ELVI did not differ between SH and NT men but was 23% (P = 0.001) lower in SH vs. NT women. EaI/ELVI did not differ between SH and NT men or women at peak exercise or during recovery. Nevertheless, EaI/ELVI reserve was 61% (P < 0.001) lower in SH vs. NT women. Similarly, resting SBP (as a continuous variable) was not associated with EaI/ELVI in men (β = −0.12, P = 0.17) but was inversely associated with EaI/ELVI in women (β = −0.47, P < 0.001). SH and a higher resting brachial SBP are associated with a lower EaI/ELVI at rest in women but not in men, and SH women have an attenuated EaI/ELVI reserve. Whether a smaller EaI/ELVI reserve leads to functional limitations warrants further examination.
Keywords: arterial elastance, left ventricular end-systolic elastance, systolic hypertension, exercise, sex
systolic hypertension (SH) is the most common form of hypertension, affecting ∼94% of hypertensive individuals over 50 yr of age (12). SH is associated with structural and functional alterations in the central arteries (28, 30) and in the left ventricle (LV) (28, 33) that are sex specific (20) and are thought to be, at least in their early stages, adaptive in nature (11). SH is a major risk factor for cardiovascular (CV) diseases, including heart failure with a normal ejection fraction (19). The specific mechanisms that underlie the transition of a hypertensive LV to a failing LV have not been completely elucidated (4), suggesting that further insights into LV performance in SH, both at rest and during exercise, are needed.
It is well established that LV performance is influenced by the arterial load and that the arterial properties are, in turn, influenced by LV performance (16, 41). Traditionally, LV performance has been evaluated in the time domain, whereas arterial load has been assessed in the frequency domain, thus limiting the ability to evaluate the cross talk between the LV and the arterial system. The pioneering work of Sunagawa et al. (41) showed, in an isolated canine heart model, that the arterial load could be globally characterized in the time domain as effective arterial elastance (EaI). EaI incorporates peripheral vascular resistance, total lumped arterial compliance, characteristic impedance, and systolic and diastolic time intervals. Furthermore, Sagawa et al. (36) showed, in an isolated canine-heart model, that LV performance could be described by LV end-systolic elastance (ElVI). ElVI is determined from the slope of the end-systolic pressure-volume relationship and is a load-independent measure of LV chamber performance. Subsequent studies have shown that EaI and ELVI can also be examined in humans both invasively (8, 10) and noninvasively (7, 17, 31). Importantly, the ratio EaI/ELVI was found to be a useful index of the interaction between the LV and the arterial system (41).
Previous studies in healthy individuals have shown that, at rest, EaI/ELVI is tightly controlled within a narrow range (39) across a broad age spectrum (27, 31) and even across species (23, 44). This tight coupling allows the CV system to optimize energetic efficiency (39). During exercise, EaI/ELVI decreases due to disproportionate increases in ELVI vs. EaI to ensure that cardiac performance is augmented sufficiently to meet the increased demands for blood flow (27). The reduction in EaI/ELVI during exercise has been shown to differ by age and by sex (27).
The objectives of this study were to 1) investigate the sex-specific association of SH and resting systolic blood pressure (SBP) (as a continuous variable) with EaI/ELVI and its components, EaI and ELVI, at rest, during exercise, and during early recovery; 2) compare the effects of brachial SBP on EaI and ELVI between men and women to gain mechanistic insights into sex differences in the impact of brachial SBP on EaI/ELVI; and 3) examine the impact of resting SBP on cardiac energetics at rest, during exercise, and recovery.
METHODS
Study population.
The study population consisted of community dwelling volunteers mainly from the Baltimore Longitudinal Study of Aging (38) who underwent rest and exercise multigated blood pool scans. All subjects in the current investigation were more than 40 yr of age with a resting ejection fraction >50%. Eighty-two percent of our subjects were Caucasian, and 75% had college degrees with above-average income and access to medical care (38). All subjects were free of CV disease as determined by detailed history and physical examination, normal resting and treadmill exercise electrocardiograms, and the absence of perfusion abnormality on thallium scintigraphy during treadmill stress testing in all men and in women over 50 yr of age. No subject was taking any cardiac or antihypertensive medication. The study conforms to the principles outlined in the Declaration of Helsinki and was approved by the institutional review boards. All subjects provided written informed consent to participate.
Evaluations.
All subjects underwent a symptom-limited upright graded exercise protocol on an electronically braked cycle ergometer, starting at a workload of 25 W and increasing by 25 W every 3 min until exhaustion. Pedal speed was maintained constant at 60 rpm. Maximal workload was defined as the maximal wattage attained during the exercise test. During the recovery period, subjects ceased pedaling and remained in the upright seated position for ∼5 min. SBP and diastolic blood pressure (DBP) were measured with cuff sphygmomanometry at seated rest, during each stage of exercise, and during the postexercise recovery period 3–5 min postexercise. End-systolic pressure (ESP) was approximated as 0.9 × brachial SBP, a noninvasive estimate of ESP that accurately predicts LV pressure-volume loop measurements of ESP (17).
Cardiac volumes at seated rest (upright seated position), during each stage of exercise, and during the recovery period (3–5 min postexercise) were determined with multigated blood pool scans as previously described (37). All cardiac volumes were normalized to body surface area, yielding their respective indexes: end-systolic volume index (ESVI) and stroke volume index (SVI). The coefficients of variation for the cardiac volumes in our laboratory were 8.6 and 6.4% at rest and at peak exercise, respectively (29, 32).
The indexes of arterial and ventricular elastance were calculated as 1) arterial elastance index (EaI) = ESP/SVI, 2) LV end-systolic elastance index (ELVI) = ESP/ESVI, and 3) arterial-ventricular coupling ratio (EaI/ELVI) = ESVI/SVI (41). Reserve was defined as the difference in these variables between rest and peak exercise. Stroke work index (SWI) was calculated as SVI × ESP (6). Pressure-volume area (PVA), an index of LV oxygen consumption (39), was calculated as SWI + potential energy [defined as ESP × (ESVI − V0)/2] (6), wherein V0, the volume-axis intercept of the end-systolic pressure volume relationship, was assumed to be zero, as previously reported (9). Systemic vascular resistance index (SVRI) was calculated as mean arterial pressure/cardiac index × 80. Leisure time physical activity (LTPA) was self-reported based on the amount of time spent performing 97 activities over the last 2 yr (24) as previously described (43).
Statistical analysis.
Subjects were classified as either normotensive (NT, n = 203), defined by a resting SBP <140 mmHg and diastolic blood pressure (DBP) <90 mmHg, or SH (n = 79), defined by SBP ≥140 mmHg. Because very few subjects had isolated diastolic hypertension, they were excluded from the analyses. The clinical characteristics of NT and SH subjects and their CV parameters measured at rest, at submaximal workloads, at peak exercise, and during recovery were compared with analyses of variance that were adjusted for age. After data from NT and SH subjects were pooled, the relationships between resting brachial SBP (as a continuous variable) and EaI/ELVI, its components EaI and ELVI, SWI, and PVA at rest, at peak exercise, and during recovery were examined by linear regression analyses that were adjusted for age. An interaction term between SBP and sex was used to examine whether the slopes of the regression lines differed between men and women. All analyses were performed with the statistical package SPSS version 13 (SPSS, Chicago, IL).
RESULTS
Baseline characteristics.
The study cohort consisted of 163 men (111 NT, 52 SH) and 119 women (92 NT, 27 SH) (Table 1). SH men and women were on average 7 and 13 yr older (P < 0.001) than their respective NT counterparts. Their average SBPs were 25 and 28% higher (P < 0.001) and their DBPs were 17 and 15% higher (P < 0.001) than in NT men and women, respectively (Table 1). Cardiac index and maximal workload did not significantly differ between NT and SH men or women after the analyses were adjusted for age. Furthermore, LTPA scores did not differ between NT and SH men or women.
Table 1.
Clinical characteristics of the study cohort
|
Men |
Women
|
|||
|---|---|---|---|---|
| NT | SH | NT | SH | |
| n | 111 | 52 | 92 | 27 |
| Age, yr | 60±11.6 | 67±10.1* | 55±12.2 | 68±13.0* |
| Height, cm | 176.5±6.1 | 174.7±6.4 | 163.8±7.5 | 160.1±6.5 |
| Weight, kg | 79.0±12.0 | 80.9±12.0 | 65.3±10.8 | 65.1±13.3 |
| Body mass index, kg/m2 | 25.3±3.1 | 26.5±3.4† | 24.4±3.9 | 25.3±4.6 |
| Body surface area, m2 | 1.95±0.16 | 1.96±0.16 | 1.70±0.15 | 1.67±0.18 |
| Systolic blood pressure, mmHg | 122±10.7 | 152±9.3‡ | 116±11.5 | 149±8.8‡ |
| Diastolic blood pressure, mmHg | 77±8.3 | 90±10.3‡ | 74±7.7 | 85±8.1‡ |
| Ejection fraction, % | 64±0.07 | 66±0.07 | 66±0.07 | 72±0.06‡ |
| Maximal workload, W | 134±35 | 129±32 | 106±36 | 78±29 |
Data are means ± SD determined in normotensive (NT) and systolic hypertensive (SH) subjects.
P < 0.001, SH men or women vs. their NT counterparts.
P < 0.01;
P < 0.001, SH men or women vs. their NT counterparts after age adjustment.
Comparison of arterial-ventricular coupling ratio and its components between SH and NT subjects at rest.
The values of EaI/ELVI, its components, and their determinants measured at rest, at submaximal stages including 50% of peak, and at peak exercise for NT and SH men and women are listed in Table 2. EaI/ELVI at rest did not differ between NT and SH men (Fig. 1A). In sharp contrast, EaI/ELVI was 21% lower (P < 0.001) in SH compared with NT women (Fig. 1A). Examining the components of this ratio, SH men had tandemly higher EaI and ELVI compared with NT men (Fig. 1, B and C). SH women also had higher EaI and ELVI compared with NT women (Fig. 1, B and C); however, the increase in ELVI in SH women was disproportionately greater than the increase in EAI, resulting in the lower EaI/ELVI.
Table 2.
Arterial-ventricular coupling ratio, its components, and their determinants at rest and during exercise in NT and SH men and women
|
Men |
Women
|
|||
|---|---|---|---|---|
| NT | SH | NT | SH | |
| EaI/ELVI | ||||
| Rest | 0.58±0.16 | 0.54±0.17 | 0.52±0.17 | 0.41±0.11‡ |
| 25 W | 0.45±0.13 | 0.44±0.16 | 0.38±0.16 | 0.35±0.14 |
| 50 W | 0.40±0.14 | 0.37±0.15 | 0.34±0.13 | 0.30±0.16 |
| 50% | 0.37±0.15 | 0.35±0.15 | 0.32±0.14 | 0.30±0.14 |
| Peak | 0.34±0.19 | 0.34±0.16 | 0.27±0.13 | 0.30±0.19 |
| Reserve | −0.23±0.19 | −0.20±0.16 | −0.26±0.15 | −0.10±0.19‡ |
| EaI, mmHg·ml−1·m−2 | ||||
| Rest | 2.32±0.52 | 2.98±0.48§ | 2.26±0.47 | 2.63±0.55† |
| 25 W | 2.33±0.52 | 2.84±0.55§ | 2.43±0.58 | 2.52±0.53 |
| 50 W | 2.40±0.53 | 2.88±0.62§ | 2.54±0.65 | 2.64±0.58 |
| 50% | 2.57±0.57 | 3.02±0.69§ | 2.56±0.60 | 2.60±0.57 |
| Peak | 3.15±0.73 | 3.52±0.80§ | 2.94±0.74 | 2.86±0.60 |
| Reserve | 0.82±0.59 | 0.53±0.66† | 0.67±0.56 | 0.27±0.69† |
| ELVI, mmHg·ml−1·m−2 | ||||
| Rest | 4.26±1.29 | 6.08±2.15§ | 4.73±1.84 | 7.06±2.74§ |
| 25 W | 5.66±2.00 | 7.43±3.16§ | 7.98±7.52 | 8.80±5.78 |
| 50 W | 6.73±2.97 | 9.13±4.10§ | 8.95±5.74 | 15.35±21.35 |
| 50% | 8.12±3.51 | 10.37±4.82§ | 9.77±5.85 | 12.71±12.04 |
| Peak | 13.21±16.45 | 16.27±18.64 | 15.49±14.20 | 17.82±25.03 |
| Reserve | 9.03±16.18 | 10.14±18.17 | 10.81±13.60 | 11.11±24.36 |
| ESVI, ml/m2 | ||||
| Rest | 27.7±7.6 | 24.8±7.2‡ | 24.3±6.5 | 21.5±7.1 |
| 25 W | 25.8±7.7 | 23.6±8.3* | 21.0±7.5 | 20.7±8.2 |
| 50 W | 24.5±8.3 | 21.0±8.1‡ | 19.5±6.9 | 18.9±10.4 |
| 50% | 22.0±8.4 | 19.9±8.2† | 18.8±7.7 | 18.5±9.6 |
| Peak | 20.4±10.7 | 19.6±9.7 | 15.4±7.1 | 18.2±11.1 |
| Reserve | −7.3±8.9 | −5.2±7.3 | −9.0±6.7 | −2.8±9.7† |
| SVI, ml/m2 | ||||
| Rest | 48.4±9.54 | 47.1±7.97 | 47.9±9.2 | 52.8±10.5‡ |
| 25 W | 58.3±11.12 | 55.5±10.68‡ | 56.1±13.2 | 60.0±11.6 |
| 50 W | 61.3±10.67 | 58.4±11.73† | 59.0±11.6 | 62.3±11.8† |
| 50% | 61.7±11.70 | 58.5±11.12† | 60.8±11.9 | 62.3±12.4 |
| Peak | 60.1±11.70 | 58.8±12.17 | 60.0±11.7 | 61.3±10.4 |
| Reserve | 11.7±10.07 | 11.8±9.81 | 12.4±8.4 | 9.0±9.2 |
| EDVI, ml/m2 | ||||
| Rest | 76.5±14.2 | 71.8±11.1‡ | 72.2±12.0 | 74.2±15.7 |
| 25 W | 84.5±14.8 | 78.7±14.3§ | 77.6±14.4 | 80.7±16.2 |
| 50 W | 86.2±15.4 | 79.3±14.9§ | 78.5±14.2 | 81.1±17.9 |
| 50% | 83.9±14.7 | 78.3±14.8§ | 79.2±14.0 | 80.8±18.7 |
| Peak | 80.9±16.8 | 78.3±17.9† | 75.5±13.7 | 79.4±16.4 |
| Reserve | 5.0±13.4 | 6.7±12.7 | 3.6±10.3 | 6.2±12.1 |
| ESP, mmHg | ||||
| Rest | 110±9.8 | 137±8.4§ | 105±10.4 | 134±7.9§ |
| 25 W | 133±13.5 | 152±15.0§ | 132±15.7 | 146±16.9† |
| 50 W | 143±15.4 | 164±19.3§ | 143±19.6 | 162±19.2 |
| 50% | 153±18.1 | 171±21.0§ | 149±19.2 | 158±19.3 |
| Peak | 183±24.8 | 200±22.5§ | 168±20.6 | 173±24.7 |
| Reserve | 73±23.3 | 63±22.3† | 64±19.1 | 39±22.8§ |
| HR, beats/min | ||||
| Rest | 66±9.0 | 70±12.2‡ | 70±9.9 | 67±10.6 |
| 25 W | 89±10.6 | 91±11.6‡ | 99±14.3 | 100±18.1 |
| 50 W | 99±12.6 | 100±11.5 | 114±16.1 | 117±19.8 |
| 50% | 109±14.6 | 108±12.7 | 120±16.6 | 111±19.0 |
| Peak | 146±22.8 | 140±19.8 | 148±22.1 | 137±19.8 |
| Reserve | 81±22.5 | 70±22.0† | 80±23.8 | 70±18.3 |
| CI, l·min·m−2 | ||||
| Rest | 3.2±0.6 | 3.3±0.7 | 3.3±0.6 | 3.5±0.9* |
| 25 W | 5.2±1.0 | 5.1±1.0 | 5.5±1.4 | 6.0±1.7* |
| 50 W | 6.1±1.3 | 5.8±1.2 | 6.6±1.4 | 7.3±1.7† |
| 50% | 6.7±1.4 | 6.3±1.2* | 7.2±1.6 | 6.9±1.9 |
| Peak | 8.8±2.0 | 8.2±1.7 | 8.9±2.3 | 8.3±1.9 |
| Reserve | 5.6±1.8 | 4.9±1.7 | 5.6±2.1 | 4.9±1.7 |
| SVRI, dyn·s−1·cm−5·m−2 | ||||
| Rest | 2,405±569 | 2,803±574§ | 2,193±485 | 2,547±597* |
| 25 W | 1,667±367 | 1,964±405§ | 1,568±346 | 1,678±372 |
| 50 W | 1,512±360 | 1,743±326§ | 1,369±289 | 1,434±300 |
| 50% | 1,431±330 | 1,655±295§ | 1,293±300 | 1,520±359 |
| Peak | 1,253±335 | 1,444±388‡ | 1,158±377 | 1,313±241 |
| Reserve | −1,155±518 | −1,351±598† | −1,034±420 | −1,246±590† |
| SWI, mmHg·ml·m−2 | ||||
| Rest | 5,373±1,207 | 6,483±1,293§ | 5,020±1,135 | 7,054±1,410§ |
| 25 W | 7,852±1,756 | 8,426±1,735 | 7,411±1,973 | 8,772±1,883‡ |
| 50 W | 8,853±1,921 | 9,609±2,230 | 8,462±1,904 | 10,187±1,800‡ |
| 50% | 9,356±2,154 | 9,985±2,108 | 9,062±2,035 | 9,889±2,012† |
| Peak | 10,970±2,703 | 11,893±2,854 | 10,092±2,335 | 11,014±2,617‡ |
| Reserve | 5,605±2,507 | 5,374±2,621 | 5,055±1,807 | 3,791±2,064 |
| PVA, mmHg·ml·m−2 | ||||
| Rest | 6,901±1,461 | 8,183±1,745§ | 6,281±1,253 | 8,490±1,706§ |
| 25 W | 9,543±1,998 | 10,232±2,024 | 8,780±2,098 | 10,277±2,146† |
| 50 W | 10,597±2,168 | 11,336±2,519 | 9,839±2,025 | 11,743±1,937§ |
| 50% | 11,127±2,322 | 11,677±2,463 | 10,440±2,147 | 11,355±2,296† |
| Peak | 12,818±2,997 | 13,843±3,396 | 11,369±2,401 | 12,711±2,953§ |
| Reserve | 5,963±2,597 | 5,613±2,926 | 5,076±1,858 | 4,010±2,091 |
EaI/ELVI, arterial-ventricular coupling ratio; EaI, effective arterial elastance; ELVI, left ventricular end-systolic elastance; ESVI, end-systolic volume index; SVI, stroke volume index; EDVI, end-diastolic volume index; ESP, end-systolic pressure; HR, heart rate; CI, cardiac index; SVRI, systemic vascular resistance index; SWI, stroke work index; PVA, pressure-volume area.
P < 0.07;
P < 0.05;
P < 0.01;
P < 0.001, SH men or women vs. their NT counterparts after adjustment for age.
Fig. 1.
Arterial-ventricular coupling ratio (EaI/ELVI; A), effective arterial elastance (EaI; B), and left ventricular (LV) end-systolic elastance (ELVI; C) measured at rest. Data are means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001, normotensive (NT) vs. systolic hypertensive (SH) subjects after adjustment for age.
The differences in resting EaI/ELVI, EAI, and ELVI between NT and SH women were not due to the older age of SH women, since our analyses were adjusted for age, and we obtained similar results when we repeated the analyses in a subset of NT and SH women who were matched for age. Furthermore, these differences were not due to anthropometric differences between NT and SH women, since we obtained similar results when the analyses were adjusted for height and weight (or body mass index) (data not shown).
Comparison of arterial-ventricular coupling ratio and its components between SH and NT subjects at peak exercise.
During exercise, EaI/ELVI decreased to augment CV performance. In both men and women, EaI/ELVI did not differ between SH and NT at peak exercise (Fig. 2, A and B). In men, this was because EaI and ELVI were tandemly higher [11%, P < 0.001, and 19%, P = not significant (NS), respectively] in SH compared with NT subjects (Fig. 1, C and E), whereas in women, EaI and ELVI did not differ between SH and NT subjects at peak exercise (Fig. 1, D and F). These differences at peak exercise were not due to the older age of SH women, since our analyses were adjusted for age, and we obtained similar results when we repeated the analyses in a subset of NT and SH women who were matched for age and maximal workload.
Fig. 2.
EaI/ELVI (A and B), EaI (C and D), ELVI (E and F), end-systolic pressure (ESP; G and H), and heart rate (HR; I and J) measured at rest, at 50% of maximal workload (50%MWL), and at peak exercise in NT and SH men and women. Data are means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001, NT vs. SH after adjustment for age.
Comparison of the coupling ratio reserve and its components between SH and NT subjects.
As expected from examining the association of SH with EaI/ELVI at rest and peak exercise, EaI/ELVI reserve did not differ between SH and NT men. In contrast, the EaI/ELVI reserve was 61% smaller (P = 0.02) in SH compared with NT women (Fig. 3A). This was entirely due to a 60% smaller increase (P < 0.05) in EaI from rest to peak exercise in SH women (Fig. 3B), since the change in ELVI from rest to peak exercise did not differ between SH and NT women (Fig. 3C). Interestingly, SH men and women had a greater reduction in SVRI from rest to peak exercise than NT subjects (Fig. 3D). Similar patterns were observed when we examined the change in EaI/ELVI, EaI, ELVI, and SVRI from rest to 50 W (data not shown).
Fig. 3.
Changes in EaI/ELVI (A), EaI (B), ELVI (C), and systemic vascular resistance index (SVRI; D) reserve (peak exercise minus rest) in NT and SH men and women. Data are means ± SE. *P < 0.05; **P < 0.01, NT vs. SH after adjustment for age.
Comparison of the coupling ratio and its components between SH and NT subjects during recovery.
During early recovery, data were available for a subset of 111 men (88 NT, 32 SH) and 85 women (68 NT, 17 SH). In both men and women, EaI/ELVI did not differ between SH and NT subjects, because in men, EaI and ELVI were tandemly higher (15%, P < 0.01, and 19%, P = NS, respectively) in SH compared with NT subjects, whereas in women, EaI and ELVI did not differ between SH and NT subjects (Fig. 4).
Fig. 4.
EaI/ELVI (A), EaI (B), ELVI (C) measured during early recovery from peak exercise in NT and SH men and women. Data are means ± SE. **P < 0.01, NT vs. SH after adjustment for age.
Effects of brachial SBP on the coupling ratio and its components.
Having identified differences in EaI/ELVI at rest between SH and NT women but not men, we next evaluated the relationship between EaI/ELVI and resting SBP as a continuous variable by pooling NT and SH data together. When both men and women were included in the analyses, there was a significant interaction (P = 0.02) between SBP and sex, indicating that the relationship between SBP and EaI/ELVI at rest differed according to sex. In men, SBP and EaI/ELVI were not associated (β coefficient = −0.12, P = 0.17), but in women, SBP and EaI/ELVI were inversely associated (β coefficient = −0.47, P < 0.001).
Insights into the sex difference in the relationship between SBP and EaI/ELVI at rest can be gleaned from examining the components of EaI/ELVI. The association of EaI and resting SBP did not differ between men and women (sex-SBP interaction, P = NS). In contrast, the association of ELVI and SBP at rest was steeper in women than in men (sex-SBP interaction, P = 0.07). Thus, in men, the absence of an association between SBP and EaI/ELVI at rest was due to tandem increases in EaI and ELVI with increasing SBP, whereas in women, the inverse association between SBP and EaI/ELVI was due to a disproportionate increase in ELVI vs. EaI with increasing SBP. Similar to the findings comparing NT with SH subjects, when resting SBP was considered as a continuous variable, there were no associations between resting SBP and EaI/ELVI at peak exercise or during recovery in either men or women.
Impact of resting brachial SBP on cardiac energetics.
In both men and women, resting SBP was positively associated with resting SWI (P < 0.001) and PVA (P < 0.001), suggesting that higher SBP requires higher oxygen consumption. In women, but not men, resting SBP was associated with peak exercise SWI (P < 0.001) and peak exercise PVA (P < 0.001). In women, this elevated energetic requirement with higher SBP persisted during early recovery, since resting SBP was also associated with recovery SWI (P < 0.001) and recovery PVA (P < 0.001). Of note, similar findings were observed when the analyses were repeated after stratification by SH status, whereby SH women had a higher SWI and PVA at rest, peak exercise, and during recovery than NT women.
DISCUSSION
The major findings of this study are that 1) SH women, but not men, had a lower resting EaI/ELVI and EaI/ELVI reserve than NT women; 2) in both men and women, EaI/ELVI at peak exercise and during recovery did not differ between SH and NT subjects; 3) in women, but not in men, resting brachial SBP was inversely associated with EaI/ELVI at rest, due to a disproportionate increase in ELVI vs. EaI with increasing SBP; and 4) in women, but not in men, a higher resting brachial SBP was associated with a higher energetic requirement at peak exercise and during recovery.
Arterial-ventricular coupling at rest.
In the resting state, previous studies have shown that EaI/ELVI is tightly controlled within a narrow range to optimize energetic efficiency (39, 42). In a previous study, Cohen-Solal et al. (9) showed that overall, EaI/ELVI at rest did not differ between hypertensive (blood pressure >160/90 mmHg) and NT men, which was similar to our findings in men. Importantly, our study is the first to examine the effects of SH on EaI/ELVI in women; we found that SH women have a markedly lower resting EaI/ELVI compared with NT women. Furthermore, we extended these findings to show that they are applicable even when SBP is used as a continuous variable.
Beyond comparing EaI/ELVI between NT and SH subjects at rest, we also compared its components. We found that both SH men and women had higher EaI and ELVI than NT men and women. Interestingly, in men, SH resulted in matched increases in EaI and ELVI, as was previously noted (9). In contrast, SH women demonstrated a disproportionate increase in ELVI compared with EaI, suggesting an adaptation by these women to limit the impact of SH on the vasculature or, alternatively, a more pronounced impact of SH on ventricular vs. arterial elastance. The latter could, in part, be related to wave reflections, which are known to be greater in women than in men (1, 3, 13, 26, 28). A previous study examining EaI and ELVI did not observe this pattern in hypertensive women, perhaps because men and women were not analyzed separately and/or participants were on antihypertensive medications (25), which may attenuate the association between SH and ELVI; our study was restricted to subjects not on medications. Of note, ELVI is determined not only by the contractility of the LV but also by structural changes such as alterations in chamber size [end-diastolic volume index (EDVI)], wall thickness, or myocardial fibrosis in response to increased afterload (15). Our results were unchanged when the analyses were repeated after ELVI was normalized for EDVI (31), suggesting that the higher ELVI likely reflects increased LV contractility. Nevertheless, because echocardiography was not performed in our study, cardiac remodeling could not be directly evaluated.
Redfield et al. (31) reported that the age-associated increase in resting ELVI was steeper in women than in men, which accounted for the more pronounced decline in EaI/ELVI with age in women than in men. We extended these findings to show that the brachial SBP-associated increase in ELVI, but not EaI, was also steeper in women than in men, even when ELVI was normalized to EDVI, which explained the more pronounced decline in EaI/ELVI with increasing SBP in women than men. Future studies should examine whether this difference is related to sex differences in structural remodeling, inotropic properties, wave reflections, or other factors.
Arterial-ventricular coupling during exercise and recovery.
During exercise, EaI/ELVI decreases to ensure that cardiac performance is augmented sufficiently to meet the increased demands for systemic blood flow (27). This is the first study to examine whether SH or SBP impact on EaI/ELVI during exercise. We found that EaI/ELVI did not significantly differ between NT and SH men or women, or with increasing SBP, at 50% of peak workload, at peak exercise, or during recovery. This suggests that CV performance at peak exercise is not affected by SH (or SBP) in persons without cardiac disease.
Although NT and SH women were able to achieve the same peak exercise EaI/ELVI, the lower baseline EaI/ELVI in SH women resulted in a marked reduction in the EaI/ELVI reserve. NT and SH women also had a similar EaI at peak exercise, even though SH women had a higher EaI at baseline. Thus the greater decline in SVRI from rest to peak exercise in SH women could represent a compensatory mechanism to limit the increase in EaI during exercise.
Energetics and SH.
SWI is an index of the amount of work performed by the heart (39). Previous studies have shown that PVA and myocardial oxygen demand are linearly related (40); therefore, PVA has been used as an index of the oxygen cost of performing cardiac work (39). In both men and women at rest, a higher SBP was associated with higher energetic requirements (i.e., SWI and PVA). Furthermore, in women, higher resting SBP was associated with higher energetic requirements at peak exercise and during recovery, which suggests that women with higher resting SBP require a greater energetic requirement irrespective of their level of activity. It is currently not known whether long-term consumption of higher energy could lead to energetic depletion (“burn out”) in the heart (14).
Clinical implications.
SH is the most common risk factor for heart failure with a normal ejection fraction, which is more prevalent in older women than in men (19). Patients with this syndrome have a lower EaI/ELVI due to a disproportionately higher ELVI than EaI (5) and a diminished CV reserve (5, 18). It is therefore of interest that the SH women in our study, none of whom had a clinical history of congestive heart failure, had a lower resting EaI/ELVI than NT women and a significantly diminished CV reserve, evident as a reduced EaI/ELVI reserve. This raises the possibility that SH women may be on a trajectory to subclinical (stage B) heart failure with impending progressive exercise intolerance and functional limitations. Furthermore, this raises the concern that a superimposed insult that adversely influences rest or peak EaI/ELVI (e.g., an acute rise in blood pressure or a myocardial infarction) could further affect the EaI/ELVI exercise reserve and, in turn, have an impact on CV function and adversely affect the quality of life of these SH women.
Study limitations.
Several limitations deserve mentioning. The indexes of arterial and ventricular elastance and of energetics were all assessed noninvasively. Some of the assumptions involved in the calculation of these parameters are discussed in the Appendix. However, this approach has been used in prior noninvasive evaluations (10, 34), and importantly, the values of EaI/ELVI, ELVI, and EaI at rest in our NT subjects are similar to those obtained invasively (10, 35). Moreover, we did not measure central blood pressure in this study. Brachial SBP overestimates central SBP, due to the phenomenon of blood pressure amplification (45), which is more pronounced in younger than older individuals. However, the formula used for noninvasive estimation of EaI/ELVI does not include a blood pressure component, and the formulas used for noninvasive estimation of EaI and ELVI include ESP calculated as 0.9 × SBP, which has previously been shown to closely approximate central ESP (17). Furthermore, the accuracy of DBP during exercise has been questioned (21); however, DBP does not affect the values of EaI/ELVI. In addition, the time point for the measurement of the cardiac and hemodynamic variables during recovery was not standardized. Instead, the measurements were performed between 3 and 5 min postexercise. Last, we classified our subjects into NT and SH groups based on a single resting blood pressure measurement, and we did not distinguish between subjects with isolated SH vs. those with mixed systolic-diastolic hypertension. A clinical diagnosis of hypertension typically requires elevated blood pressure on at least two occasions. Nonetheless, we examined the relationship between EaI/ELVI and resting SBP (as a continuous variable) and found results similar to those analyses that stratified subjects into NT and SH groups.
Conclusion.
SH and a higher resting brachial SBP are associated with a lower EaI/ELVI at rest in women but not in men, and they do not affect EaI/ELVI during exercise or recovery. Women with SH or with increasing resting SBP have an elevated energetic requirement at rest, at peak exercise, and during recovery, and they also have a markedly attenuated EaI/ELVI reserve. This diminished EaI/ELVI reserve may lead to future functional limitations and warrants further examination.
GRANTS
This research was supported in part by the Intramural Research Program of the National Institute on Aging. V. Melenovsky is currently supported by Czech Republic State Department of Health Grant MZO-00023001.
APPENDIX
Estimation of V0.
In this noninvasive study we assumed V0 to be negligible compared with ESV in the calculation of ELVI. However, V0 is not well characterized in humans, especially during exercise. Differences in V0 between NT and SH could have significant implications on the findings of our study. One previous study, in relatively healthy subjects, showed that V0 at rest equaled 14% of ESVI (2). We therefore recalculated ELVI at rest while including V0 and assuming that NT women had a resting V0 that equaled 15% of ESVI. Because we did not know whether V0 in SH women was higher or lower than in NT women at rest, we allowed V0 in SH women to be either 50% lower or 50% higher than V0 in NT women. Importantly, in both cases, resting ELVI remained significantly higher, and resting EaI/ELVI remained significantly lower, in SH than NT women.
Two studies have examined the change in V0 during stress. In 11 healthy adult dogs, Little and Cheng (22) found that although the absolute values of V0 did not significantly change during exercise, V0 as a percentage of ESV increased by 9%. In contrast, in seven healthy subjects, Starling (39) found that V0 both in absolute values and as a percentage of ESV did not appreciably change during dobutamine infusion. Therefore, we recalculated ELVI at peak exercise and assumed that V0 as a percentage of ESVI either did not change from rest to peak exercise or increased by 10% in NT women. Furthermore, since we did not know whether V0 in SH women was higher or lower than in NT women at peak exercise, we allowed V0 in SH women to be either 50% lower or 50% higher than V0 in NT women. Importantly, in all cases, no differences were found at peak exercise in ELVI or EaI/ELVI between NT and SH women. Similarly, our results were not changed when these analyses were repeated in men, both at rest and at peak exercise, using the aforementioned assumptions. Thus the findings of our study did not significantly change when we assumed nonnegligible values of V0 in the calculation of ELVI both at rest and at peak exercise.
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