The sex-specific impact of systolic hypertension and systolic blood pressure on arterial-ventricular...

doi: 10.1152/ajpheart.01179.2007295:H145-H153, 2008. First published 2 May 2008;Am J Physiol Heart Circ Physiol

Becker, Luigi Ferrucci, Jerome L. Fleg, Edward G. Lakatta and Samer S. NajjarPaul D. Chantler, Vojtech Melenovsky, Steven P. Schulman, Gary Gerstenblith, Lewis C.rest and during exercisesystolic blood pressure on arterial-ventricular coupling at The sex-specific impact of systolic hypertension and

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The sex-specific impact of systolic hypertension and systolic blood pressureon arterial-ventricular coupling at rest and during exercise

Paul D. Chantler,1 Vojtech Melenovsky,2 Steven P. Schulman,3 Gary Gerstenblith,3 Lewis C. Becker,3

Luigi Ferrucci,4 Jerome L. Fleg,5 Edward G. Lakatta,1 and Samer S. Najjar1

1Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health (NIH), Baltimore,Maryland; 2Department of Cardiology, Institute of Clinical and Experimental Medicine, Prague, Czech Republic; 3Divisionof Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore; 4Longitudinal Studies Section,Clinical Research Branch, National Institute on Aging, NIH, Baltimore; and 5Division of Cardiovascular Diseases, NationalHeart, Lung, and Blood Institute, Bethesda, Maryland

Submitted 10 October 2007; accepted in final form 28 April 2008

Chantler PD, Melenovsky V, Schulman SP, Gerstenblith G,Becker LC, Ferrucci L, Fleg JL, Lakatta EG, Najjar SS. Thesex-specific impact of systolic hypertension and systolic blood pres-sure on arterial-ventricular coupling at rest and during exercise. Am JPhysiol Heart Circ Physiol 295: H145–H153, 2008. First publishedMay 2, 2008; doi:10.1152/ajpheart.01179.2007.—In healthy subjectsthe arterial system and the left ventricle (LV) are tightly coupled atrest to optimize cardiac performance. Systolic hypertension (SH) is amajor risk factor for heart failure and is associated with structural andfunctional alterations in the arteries and the LV. The effects of SH andresting systolic blood pressure (SBP) on arterial-ventricular coupling(EaI/ELVI) at rest, at peak exercise, and during recovery are not welldescribed. We noninvasively characterized EaI/ELVI as end-systolicvolume index/stroke volume index in subjects who were normoten-sive (NT, n � 203) or had SH (brachial SBP �140 mmHg, n � 79).Cardiac volumes were measured at rest and throughout exhaustiveupright cycle exercise with gated blood pool scans. EaI/ELVI reservewas 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 betweenSH 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 notassociated with EaI/ELVI in men (� � �0.12, P � 0.17) but wasinversely associated with EaI/ELVI in women (� � �0.47, P �0.001). SH and a higher resting brachial SBP are associated with alower EaI/ELVI at rest in women but not in men, and SH women havean attenuated EaI/ELVI reserve. Whether a smaller EaI/ELVI reserveleads to functional limitations warrants further examination.

arterial elastance; left ventricular end-systolic elastance; systolic hy-pertension; exercise; sex

SYSTOLIC HYPERTENSION (SH) is the most common form ofhypertension, affecting �94% of hypertensive individuals over50 yr of age (12). SH is associated with structural and func-tional alterations in the central arteries (28, 30) and in the leftventricle (LV) (28, 33) that are sex specific (20) and arethought to be, at least in their early stages, adaptive in nature(11). SH is a major risk factor for cardiovascular (CV) dis-eases, including heart failure with a normal ejection fraction(19). The specific mechanisms that underlie the transition of ahypertensive LV to a failing LV have not been completely

elucidated (4), suggesting that further insights into LV perfor-mance in SH, both at rest and during exercise, are needed.

It is well established that LV performance is influenced bythe arterial load and that the arterial properties are, in turn,influenced by LV performance (16, 41). Traditionally, LVperformance has been evaluated in the time domain, whereasarterial load has been assessed in the frequency domain, thuslimiting the ability to evaluate the cross talk between the LVand the arterial system. The pioneering work of Sunagawaet al. (41) showed, in an isolated canine heart model, that thearterial load could be globally characterized in the time domainas effective arterial elastance (EaI). EaI incorporates peripheralvascular resistance, total lumped arterial compliance, charac-teristic 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 LVend-systolic elastance (ElVI). ElVI is determined from the slopeof the end-systolic pressure-volume relationship and is a load-independent measure of LV chamber performance. Subsequentstudies have shown that EaI and ELVI can also be examined inhumans both invasively (8, 10) and noninvasively (7, 17, 31).Importantly, the ratio EaI/ELVI was found to be a useful indexof the interaction between the LV and the arterial system (41).

Previous studies in healthy individuals have shown that, atrest, 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 optimizeenergetic efficiency (39). During exercise, EaI/ELVI decreasesdue to disproportionate increases in ELVI vs. EaI to ensure thatcardiac performance is augmented sufficiently to meet theincreased demands for blood flow (27). The reduction inEaI/ELVI during exercise has been shown to differ by age andby sex (27).

The objectives of this study were to 1) investigate thesex-specific association of SH and resting systolic blood pres-sure (SBP) (as a continuous variable) with EaI/ELVI and itscomponents, EaI and ELVI, at rest, during exercise, and duringearly recovery; 2) compare the effects of brachial SBP on EaIand ELVI between men and women to gain mechanistic insightsinto sex differences in the impact of brachial SBP on EaI/ELVI;and 3) examine the impact of resting SBP on cardiac energeticsat rest, during exercise, and recovery.

Address for reprint requests and other correspondence: S. S. Najjar, Labo-ratory of Cardiovascular Science, National Institute on Aging, NIH, 5th Floor,Harbor Hospital, 3001 S. Hanover St., Baltimore, MD 21225 (e-mail: [email protected]).

The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked “advertisement”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Am J Physiol Heart Circ Physiol 295: H145–H153, 2008.First published May 2, 2008; doi:10.1152/ajpheart.01179.2007.

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METHODS

Study population. The study population consisted of communitydwelling volunteers mainly from the Baltimore Longitudinal Study ofAging (38) who underwent rest and exercise multigated blood poolscans. All subjects in the current investigation were more than 40 yrof age with a resting ejection fraction �50%. Eighty-two percent ofour subjects were Caucasian, and 75% had college degrees withabove-average income and access to medical care (38). All subjectswere free of CV disease as determined by detailed history andphysical examination, normal resting and treadmill exercise electro-cardiograms, and the absence of perfusion abnormality on thalliumscintigraphy during treadmill stress testing in all men and in womenover 50 yr of age. No subject was taking any cardiac or antihyper-tensive medication. The study conforms to the principles outlined inthe Declaration of Helsinki and was approved by the institutionalreview boards. All subjects provided written informed consent toparticipate.

Evaluations. All subjects underwent a symptom-limited uprightgraded exercise protocol on an electronically braked cycle ergometer,starting at a workload of 25 W and increasing by 25 W every 3 minuntil exhaustion. Pedal speed was maintained constant at 60 rpm.Maximal workload was defined as the maximal wattage attainedduring the exercise test. During the recovery period, subjects ceasedpedaling and remained in the upright seated position for �5 min. SBPand diastolic blood pressure (DBP) were measured with cuff sphyg-momanometry at seated rest, during each stage of exercise, and duringthe postexercise recovery period 3–5 min postexercise. End-systolicpressure (ESP) was approximated as 0.9 � brachial SBP, a noninva-sive estimate of ESP that accurately predicts LV pressure-volumeloop measurements of ESP (17).

Cardiac volumes at seated rest (upright seated position), duringeach stage of exercise, and during the recovery period (3–5 minpostexercise) were determined with multigated blood pool scans aspreviously described (37). All cardiac volumes were normalized tobody surface area, yielding their respective indexes: end-systolicvolume index (ESVI) and stroke volume index (SVI). The coefficientsof variation for the cardiac volumes in our laboratory were 8.6 and6.4% at rest and at peak exercise, respectively (29, 32).

The indexes of arterial and ventricular elastance were calculated as1) arterial elastance index (EaI) � ESP/SVI, 2) LV end-systolicelastance index (ELVI) � ESP/ESVI, and 3) arterial-ventricular cou-pling ratio (EaI/ELVI) � ESVI/SVI (41). Reserve was defined as thedifference in these variables between rest and peak exercise. Strokework index (SWI) was calculated as SVI � ESP (6). Pressure-volumearea (PVA), an index of LV oxygen consumption (39), was calculatedas SWI � potential energy [defined as ESP � (ESVI � V0)/2] (6),wherein V0, the volume-axis intercept of the end-systolic pressurevolume relationship, was assumed to be zero, as previously reported

(9). Systemic vascular resistance index (SVRI) was calculated asmean arterial pressure/cardiac index � 80. Leisure time physicalactivity (LTPA) was self-reported based on the amount of time spentperforming 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 diastolicblood pressure (DBP) �90 mmHg, or SH (n � 79), defined by SBP�140 mmHg. Because very few subjects had isolated diastolic hy-pertension, they were excluded from the analyses. The clinical char-acteristics of NT and SH subjects and their CV parameters measuredat rest, at submaximal workloads, at peak exercise, and duringrecovery were compared with analyses of variance that were adjustedfor age. After data from NT and SH subjects were pooled, therelationships between resting brachial SBP (as a continuous variable)and EaI/ELVI, its components EaI and ELVI, SWI, and PVA at rest, atpeak exercise, and during recovery were examined by linear regres-sion analyses that were adjusted for age. An interaction term betweenSBP and sex was used to examine whether the slopes of the regressionlines differed between men and women. All analyses were performedwith the statistical package SPSS version 13 (SPSS, Chicago, IL).

RESULTS

Baseline characteristics. The study cohort consisted of 163men (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 averageSBPs were 25 and 28% higher (P � 0.001) and their DBPswere 17 and 15% higher (P � 0.001) than in NT men andwomen, respectively (Table 1). Cardiac index and maximalworkload did not significantly differ between NT and SH menor women after the analyses were adjusted for age. Further-more, LTPA scores did not differ between NT and SH men orwomen.

Comparison of arterial-ventricular coupling ratio and itscomponents between SH and NT subjects at rest. The values ofEaI/ELVI, its components, and their determinants measuredat rest, at submaximal stages including 50% of peak, and atpeak exercise for NT and SH men and women are listed inTable 2. EaI/ELVI at rest did not differ between NT and SHmen (Fig. 1A). In sharp contrast, EaI/ELVI was 21% lower (P �0.001) in SH compared with NT women (Fig. 1A). Examiningthe components of this ratio, SH men had tandemly higher EaIand ELVI compared with NT men (Fig. 1, B and C). SH womenalso had higher EaI and ELVI compared with NT women (Fig.1, B and C); however, the increase in ELVI in SH women was

Table 1. Clinical characteristics of the study cohort

Men Women

NT SH NT SH

n 111 52 92 27Age, yr 6011.6 6710.1* 5512.2 6813.0*Height, cm 176.56.1 174.76.4 163.87.5 160.16.5Weight, kg 79.012.0 80.912.0 65.310.8 65.113.3Body mass index, kg/m2 25.33.1 26.53.4† 24.43.9 25.34.6Body surface area, m2 1.950.16 1.960.16 1.700.15 1.670.18Systolic blood pressure, mmHg 12210.7 1529.3‡ 11611.5 1498.8‡Diastolic blood pressure, mmHg 778.3 9010.3‡ 747.7 858.1‡Ejection fraction, % 640.07 660.07 660.07 720.06‡Maximal workload, W 13435 12932 10636 7829

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.

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Table 2. Arterial-ventricular coupling ratio, its components, and their determinants at rest and during exercise in NTand SH men and women

Men Women

NT SH NT SH

EaI/ELVIRest 0.580.16 0.540.17 0.520.17 0.410.11‡25 W 0.450.13 0.440.16 0.380.16 0.350.1450 W 0.400.14 0.370.15 0.340.13 0.300.1650% 0.370.15 0.350.15 0.320.14 0.300.14Peak 0.340.19 0.340.16 0.270.13 0.300.19Reserve �0.230.19 �0.200.16 �0.260.15 �0.100.19‡

EaI, mmHg �ml�1 �m�2

Rest 2.320.52 2.980.48§ 2.260.47 2.630.55†25 W 2.330.52 2.840.55§ 2.430.58 2.520.5350 W 2.400.53 2.880.62§ 2.540.65 2.640.5850% 2.570.57 3.020.69§ 2.560.60 2.600.57Peak 3.150.73 3.520.80§ 2.940.74 2.860.60Reserve 0.820.59 0.530.66† 0.670.56 0.270.69†

ELVI, mmHg �ml�1 �m�2

Rest 4.261.29 6.082.15§ 4.731.84 7.062.74§25 W 5.662.00 7.433.16§ 7.987.52 8.805.7850 W 6.732.97 9.134.10§ 8.955.74 15.3521.3550% 8.123.51 10.374.82§ 9.775.85 12.7112.04Peak 13.2116.45 16.2718.64 15.4914.20 17.8225.03Reserve 9.0316.18 10.1418.17 10.8113.60 11.1124.36

ESVI, ml/m2

Rest 27.77.6 24.87.2‡ 24.36.5 21.57.125 W 25.87.7 23.68.3* 21.07.5 20.78.250 W 24.58.3 21.08.1‡ 19.56.9 18.910.450% 22.08.4 19.98.2† 18.87.7 18.59.6Peak 20.410.7 19.69.7 15.47.1 18.211.1Reserve �7.38.9 �5.27.3 �9.06.7 �2.89.7†

SVI, ml/m2

Rest 48.49.54 47.17.97 47.99.2 52.810.5‡25 W 58.311.12 55.510.68‡ 56.113.2 60.011.650 W 61.310.67 58.411.73† 59.011.6 62.311.8†50% 61.711.70 58.511.12† 60.811.9 62.312.4Peak 60.111.70 58.812.17 60.011.7 61.310.4Reserve 11.710.07 11.89.81 12.48.4 9.09.2

EDVI, ml/m2

Rest 76.514.2 71.811.1‡ 72.212.0 74.215.725 W 84.514.8 78.714.3§ 77.614.4 80.716.250 W 86.215.4 79.314.9§ 78.514.2 81.117.950% 83.914.7 78.314.8§ 79.214.0 80.818.7Peak 80.916.8 78.317.9† 75.513.7 79.416.4Reserve 5.013.4 6.712.7 3.610.3 6.212.1

ESP, mmHgRest 1109.8 1378.4§ 10510.4 1347.9§25 W 13313.5 15215.0§ 13215.7 14616.9†50 W 14315.4 16419.3§ 14319.6 16219.250% 15318.1 17121.0§ 14919.2 15819.3Peak 18324.8 20022.5§ 16820.6 17324.7Reserve 7323.3 6322.3† 6419.1 3922.8§

HR, beats/minRest 669.0 7012.2‡ 709.9 6710.625 W 8910.6 9111.6‡ 9914.3 10018.150 W 9912.6 10011.5 11416.1 11719.850% 10914.6 10812.7 12016.6 11119.0Peak 14622.8 14019.8 14822.1 13719.8Reserve 8122.5 7022.0† 8023.8 7018.3

CI, l �min �m�2

Rest 3.20.6 3.30.7 3.30.6 3.50.9*25 W 5.21.0 5.11.0 5.51.4 6.01.7*50 W 6.11.3 5.81.2 6.61.4 7.31.7†50% 6.71.4 6.31.2* 7.21.6 6.91.9Peak 8.82.0 8.21.7 8.92.3 8.31.9Reserve 5.61.8 4.91.7 5.62.1 4.91.7

SVRI, dyn � s�1 �cm�5 �m�2

Rest 2,405569 2,803574§ 2,193485 2,547597*25 W 1,667367 1,964405§ 1,568346 1,678372

Continued

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disproportionately greater than the increase in EAI, resulting inthe lower EaI/ELVI.

The differences in resting EaI/ELVI, EAI, and ELVI betweenNT and SH women were not due to the older age of SHwomen, since our analyses were adjusted for age, and weobtained similar results when we repeated the analyses in asubset of NT and SH women who were matched for age.Furthermore, these differences were not due to anthropometricdifferences between NT and SH women, since we obtainedsimilar results when the analyses were adjusted for height andweight (or body mass index) (data not shown).

Comparison of arterial-ventricular coupling ratio and itscomponents between SH and NT subjects at peak exercise.During exercise, EaI/ELVI decreased to augment CV perfor-mance. In both men and women, EaI/ELVI did not differbetween 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] inSH compared with NT subjects (Fig. 1, C and E), whereas inwomen, EaI and ELVI did not differ between SH and NTsubjects at peak exercise (Fig. 1, D and F). These differencesat peak exercise were not due to the older age of SH women,since our analyses were adjusted for age, and we obtainedsimilar results when we repeated the analyses in a subset of NTand SH women who were matched for age and maximalworkload.

Comparison of the coupling ratio reserve and its compo-nents between SH and NT subjects. As expected from exam-ining the association of SH with EaI/ELVI at rest and peakexercise, EaI/ELVI reserve did not differ between SH and NTmen. In contrast, the EaI/ELVI reserve was 61% smaller (P �0.02) in SH compared with NT women (Fig. 3A). This wasentirely due to a 60% smaller increase (P � 0.05) in EaI fromrest to peak exercise in SH women (Fig. 3B), since the changein ELVI from rest to peak exercise did not differ between SHand NT women (Fig. 3C). Interestingly, SH men and women

had a greater reduction in SVRI from rest to peak exercise thanNT subjects (Fig. 3D). Similar patterns were observed whenwe examined the change in EaI/ELVI, EaI, ELVI, and SVRIfrom rest to 50 W (data not shown).

Comparison of the coupling ratio and its components be-tween SH and NT subjects during recovery. During earlyrecovery, data were available for a subset of 111 men (88 NT,32 SH) and 85 women (68 NT, 17 SH). In both men andwomen, 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 NTsubjects, whereas in women, EaI and ELVI did not differbetween SH and NT subjects (Fig. 4).

Effects of brachial SBP on the coupling ratio and its com-ponents. Having identified differences in EaI/ELVI at rest be-tween SH and NT women but not men, we next evaluated therelationship between EaI/ELVI and resting SBP as a continuousvariable by pooling NT and SH data together. When both menand women were included in the analyses, there was a signif-icant interaction (P � 0.02) between SBP and sex, indicatingthat the relationship between SBP and EaI/ELVI at rest differedaccording to sex. In men, SBP and EaI/ELVI were not associ-ated (� coefficient � �0.12, P � 0.17), but in women, SBPand EaI/ELVI were inversely associated (� coefficient ��0.47, P � 0.001).

Insights into the sex difference in the relationship betweenSBP and EaI/ELVI at rest can be gleaned from examining thecomponents of EaI/ELVI. The association of EaI and restingSBP did not differ between men and women (sex-SBP inter-action, P � NS). In contrast, the association of ELVI and SBPat rest was steeper in women than in men (sex-SBP interaction,P � 0.07). Thus, in men, the absence of an association betweenSBP and EaI/ELVI at rest was due to tandem increases in EaIand ELVI with increasing SBP, whereas in women, the inverseassociation between SBP and EaI/ELVI was due to a dispro-portionate increase in ELVI vs. EaI with increasing SBP. Sim-

Table 2.—Continued

Men Women

NT SH NT SH

50 W 1,512360 1,743326§ 1,369289 1,43430050% 1,431330 1,655295§ 1,293300 1,520359Peak 1,253335 1,444388‡ 1,158377 1,313241Reserve �1,155518 �1,351598† �1,034420 �1,246590†

SWI, mmHg �ml �m�2

Rest 5,3731,207 6,4831,293§ 5,0201,135 7,0541,410§25 W 7,8521,756 8,4261,735 7,4111,973 8,7721,883‡50 W 8,8531,921 9,6092,230 8,4621,904 10,1871,800‡50% 9,3562,154 9,9852,108 9,0622,035 9,8892,012†Peak 10,9702,703 11,8932,854 10,0922,335 11,0142,617‡Reserve 5,6052,507 5,3742,621 5,0551,807 3,7912,064

PVA, mmHg �ml �m�2

Rest 6,9011,461 8,1831,745§ 6,2811,253 8,4901,706§25 W 9,5431,998 10,2322,024 8,7802,098 10,2772,146†50 W 10,5972,168 11,3362,519 9,8392,025 11,7431,937§50% 11,1272,322 11,6772,463 10,4402,147 11,3552,296†Peak 12,8182,997 13,8433,396 11,3692,401 12,7112,953§Reserve 5,9632,597 5,6132,926 5,0761,858 4,0102,091

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 resistanceindex; 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 afteradjustment for age.



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ilar to the findings comparing NT with SH subjects, whenresting SBP was considered as a continuous variable, therewere no associations between resting SBP and EaI/ELVI at peakexercise or during recovery in either men or women.

Impact of resting brachial SBP on cardiac energetics. Inboth men and women, resting SBP was positively associatedwith resting SWI (P � 0.001) and PVA (P � 0.001), suggest-ing that higher SBP requires higher oxygen consumption. Inwomen, 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 SBPpersisted during early recovery, since resting SBP was alsoassociated with recovery SWI (P � 0.001) and recovery PVA(P � 0.001). Of note, similar findings were observed when theanalyses were repeated after stratification by SH status,whereby SH women had a higher SWI and PVA at rest, peakexercise, and during recovery than NT women.

DISCUSSION

The major findings of this study are that 1) SH women, butnot men, had a lower resting EaI/ELVI and EaI/ELVI reservethan NT women; 2) in both men and women, EaI/ELVI at peakexercise and during recovery did not differ between SH and NTsubjects; 3) in women, but not in men, resting brachial SBPwas inversely associated with EaI/ELVI at rest, due to a dispro-portionate increase in ELVI vs. EaI with increasing SBP; and4) in women, but not in men, a higher resting brachial SBP wasassociated with a higher energetic requirement at peak exerciseand during recovery.

Arterial-ventricular coupling at rest. In the resting state,previous studies have shown that EaI/ELVI is tightly controlledwithin 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 (bloodpressure �160/90 mmHg) and NT men, which was similar toour findings in men. Importantly, our study is the first toexamine the effects of SH on EaI/ELVI in women; we foundthat SH women have a markedly lower resting EaI/ELVI com-pared with NT women. Furthermore, we extended these find-ings to show that they are applicable even when SBP is used asa continuous variable.

Beyond comparing EaI/ELVI between NT and SH subjects atrest, we also compared its components. We found that both SHmen and women had higher EaI and ELVI than NT men andwomen. Interestingly, in men, SH resulted in matched in-creases in EaI and ELVI, as was previously noted (9). Incontrast, SH women demonstrated a disproportionate increasein ELVI compared with EaI, suggesting an adaptation by thesewomen to limit the impact of SH on the vasculature or,alternatively, a more pronounced impact of SH on ventricularvs. arterial elastance. The latter could, in part, be related towave reflections, which are known to be greater in women thanin men (1, 3, 13, 26, 28). A previous study examining EaI andELVI did not observe this pattern in hypertensive women,perhaps because men and women were not analyzed separatelyand/or participants were on antihypertensive medications (25),which may attenuate the association between SH and ELVI; ourstudy was restricted to subjects not on medications. Of note,ELVI is determined not only by the contractility of the LV butalso by structural changes such as alterations in chamber size[end-diastolic volume index (EDVI)], wall thickness, or myo-cardial fibrosis in response to increased afterload (15). Ourresults were unchanged when the analyses were repeated afterELVI was normalized for EDVI (31), suggesting that the higherELVI 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 increasein resting ELVI was steeper in women than in men, which

Fig. 1. Arterial-ventricular coupling ratio (EaI/ELVI; A), effective arterialelastance (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 adjust-ment for age.



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accounted for the more pronounced decline in EaI/ELVI withage in women than in men. We extended these findings to showthat the brachial SBP-associated increase in ELVI, but not EaI,was also steeper in women than in men, even when ELVI wasnormalized to EDVI, which explained the more pronounceddecline in EaI/ELVI with increasing SBP in women than men.Future studies should examine whether this difference is re-lated to sex differences in structural remodeling, inotropicproperties, wave reflections, or other factors.

Arterial-ventricular coupling during exercise and recovery.During exercise, EaI/ELVI decreases to ensure that cardiacperformance is augmented sufficiently to meet the increaseddemands for systemic blood flow (27). This is the first study toexamine whether SH or SBP impact on EaI/ELVI during exer-cise. We found that EaI/ELVI did not significantly differ be-tween NT and SH men or women, or with increasing SBP, at50% of peak workload, at peak exercise, or during recovery.This suggests that CV performance at peak exercise is notaffected by SH (or SBP) in persons without cardiac disease.

Although NT and SH women were able to achieve the samepeak exercise EaI/ELVI, the lower baseline EaI/ELVI in SHwomen 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 thegreater decline in SVRI from rest to peak exercise in SH

women could represent a compensatory mechanism to limit theincrease in EaI during exercise.

Energetics and SH. SWI is an index of the amount of workperformed by the heart (39). Previous studies have shown thatPVA and myocardial oxygen demand are linearly related (40);therefore, PVA has been used as an index of the oxygen cost ofperforming cardiac work (39). In both men and women at rest,a higher SBP was associated with higher energetic require-ments (i.e., SWI and PVA). Furthermore, in women, higherresting SBP was associated with higher energetic requirementsat peak exercise and during recovery, which suggests thatwomen with higher resting SBP require a greater energeticrequirement irrespective of their level of activity. It is currentlynot known whether long-term consumption of higher energycould lead to energetic depletion (“burn out”) in the heart (14).

Clinical implications. SH is the most common risk factor forheart failure with a normal ejection fraction, which is moreprevalent in older women than in men (19). Patients with thissyndrome have a lower EaI/ELVI due to a disproportionatelyhigher ELVI than EaI (5) and a diminished CV reserve (5, 18).It is therefore of interest that the SH women in our study, noneof whom had a clinical history of congestive heart failure, hada lower resting EaI/ELVI than NT women and a significantlydiminished CV reserve, evident as a reduced EaI/ELVI reserve.This raises the possibility that SH women may be on a

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 maximalworkload (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 afteradjustment for age.

Fig. 3. Changes in EaI/ELVI (A), EaI (B),ELVI (C), and systemic vascular resistanceindex (SVRI; D) reserve (peak exercise mi-nus rest) in NT and SH men and women. Dataare means SE. *P � 0.05; **P � 0.01, NTvs. SH after adjustment for age.



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trajectory to subclinical (stage B) heart failure with impendingprogressive exercise intolerance and functional limitations.Furthermore, this raises the concern that a superimposed insultthat adversely influences rest or peak EaI/ELVI (e.g., an acuterise in blood pressure or a myocardial infarction) could furtheraffect the EaI/ELVI exercise reserve and, in turn, have animpact on CV function and adversely affect the quality of lifeof these SH women.

Study limitations. Several limitations deserve mentioning.The indexes of arterial and ventricular elastance and of ener-getics were all assessed noninvasively. Some of the assump-tions involved in the calculation of these parameters are dis-cussed in the Appendix. However, this approach has been usedin prior noninvasive evaluations (10, 34), and importantly, thevalues of EaI/ELVI, ELVI, and EaI at rest in our NT subjects aresimilar to those obtained invasively (10, 35). Moreover, we did

not measure central blood pressure in this study. Brachial SBPoverestimates central SBP, due to the phenomenon of bloodpressure amplification (45), which is more pronounced inyounger than older individuals. However, the formula used fornoninvasive estimation of EaI/ELVI does not include a bloodpressure component, and the formulas used for noninvasiveestimation of EaI and ELVI include ESP calculated as 0.9 �SBP, which has previously been shown to closely approximatecentral ESP (17). Furthermore, the accuracy of DBP duringexercise has been questioned (21); however, DBP does notaffect the values of EaI/ELVI. In addition, the time point for themeasurement of the cardiac and hemodynamic variables duringrecovery was not standardized. Instead, the measurements wereperformed between 3 and 5 min postexercise. Last, we classi-fied our subjects into NT and SH groups based on a singleresting blood pressure measurement, and we did not distin-guish between subjects with isolated SH vs. those with mixedsystolic-diastolic hypertension. A clinical diagnosis of hyper-tension typically requires elevated blood pressure on at leasttwo occasions. Nonetheless, we examined the relationshipbetween EaI/ELVI and resting SBP (as a continuous variable)and found results similar to those analyses that stratifiedsubjects into NT and SH groups.

Conclusion. SH and a higher resting brachial SBP areassociated with a lower EaI/ELVI at rest in women but not inmen, and they do not affect EaI/ELVI during exercise orrecovery. Women with SH or with increasing resting SBP havean elevated energetic requirement at rest, at peak exercise, andduring recovery, and they also have a markedly attenuatedEaI/ELVI reserve. This diminished EaI/ELVI reserve may lead tofuture functional limitations and warrants further examination.

APPENDIX

Estimation of V0. In this noninvasive study we assumed V0 to benegligible 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 impli-cations on the findings of our study. One previous study, in relativelyhealthy subjects, showed that V0 at rest equaled 14% of ESVI (2). Wetherefore recalculated ELVI at rest while including V0 and assumingthat NT women had a resting V0 that equaled 15% of ESVI. Becausewe did not know whether V0 in SH women was higher or lower thanin 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 bothcases, resting ELVI remained significantly higher, and resting EaI/ELVIremained significantly lower, in SH than NT women.

Two studies have examined the change in V0 during stress. In 11healthy adult dogs, Little and Cheng (22) found that although theabsolute values of V0 did not significantly change during exercise, V0

as a percentage of ESV increased by 9%. In contrast, in seven healthysubjects, Starling (39) found that V0 both in absolute values and as apercentage of ESV did not appreciably change during dobutamineinfusion. Therefore, we recalculated ELVI at peak exercise and as-sumed that V0 as a percentage of ESVI either did not change from restto peak exercise or increased by 10% in NT women. Furthermore,since we did not know whether V0 in SH women was higher or lowerthan in NT women at peak exercise, we allowed V0 in SH women tobe either 50% lower or 50% higher than V0 in NT women. Impor-tantly, in all cases, no differences were found at peak exercise in ELVIor EaI/ELVI between NT and SH women. Similarly, our results werenot changed when these analyses were repeated in men, both at restand at peak exercise, using the aforementioned assumptions. Thus thefindings of our study did not significantly change when we assumed

Fig. 4. EaI/ELVI (A), EaI (B), ELVI (C) measured during early recovery frompeak exercise in NT and SH men and women. Data are means SE. **P �0.01, NT vs. SH after adjustment for age.



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nonnegligible values of V0 in the calculation of ELVI both at rest andat peak exercise.

GRANTS

This research was supported in part by the Intramural Research Program ofthe National Institute on Aging. V. Melenovsky is currently supported byCzech Republic State Department of Health Grant MZO-00023001.

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