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Sex Differences in Cardiac Adaptation to

Isolated Systolic Hypertension


Harlan M. Krumholz, MD, Martin Larson, SCD, and Daniel Levy, MD

I
solated systolic hypertension, commonly believed to
This study exanines the association of isolated be due to stiffening of the arterial walls, exposesthe
systolic hypdemion with left ventricular (Lv) heart to increased wall stress. Increased systolic
mass and geometry in men and women. The sul+ blood pressureis associatedwith increasedleft ventricu-
jects of this study were surviting members of ths lar (LV) mass.1,2In a recent study, isolated systolic hy-
Framim Heart Study aml the Framingham Of& pertension was associatedwith increased LV mass re-
spdng Study who at&ended the index examination sulting from increased wall thickness and slightly in-
(between 1979 and 1983) and were aged 250 creasedchamber size.’ Them was no sign&ant differ-
ym free of clinkally apparent cardiovascular ence in relative wall thickness (the ratio of wall thick-
disease, not takiM antihypertensive medication ness to internal dimension) for the group with isolated
and without diastolic hypertension (diastolic systolic hypertensioncomparedwith normal control sub-
bloodpressure*90mmHg),andinwhomLVmass jects. The role of gender in cardiac adaptation to the
could be detemdned by echocardiography. Exam& stressof systolic hypertension, however, is not known.
nations routinely included l&lead restie electr4k There is experimental evidence that sex hormones have
c=wmmY, measurements of restia blood an important cardioregulatory effect and that there may
-~,--, blood glucose levels, be sex-specitic adaptations to cardiac stress.s-5Also,
mdlwlode echoczHography.M=modeecho- there is recent evidence that gender is a factor in LV
cardbgmns adequate to assess LV hypertrophy adaptationto valvular aortic stenosisin adults aged X50
wemobtainedfor1,333nommten8ivesubjects yeas6 However, there are no reports comparing LV
(538 men and 744 women) and 79 subjects with geometricpatternsin men and women with isolated sys-
isolated systolic hypertension (26 men and 53 tolic hypertension. To determine if men and women
women). Adjusthbg for age, body mass index and have different cardiac structural adaptations to isolated
diastolic blood pressure, the relatSve odds of LV systolic hypertension, we examined the association of
wP@rophy wsociated with isolated systolic hy- isolated systolic hypertension with LV mass and geom-
.
pertemm were 2.58 (95% confidence interval etry in subjectsenrolled in the Framingham Heart Study
0.97 to 6.86) in men and 5.94 (95% confk)811c8 irr and the Framingham Offspring Study.
tewal3.06 to ll.53) in women. Women with iso-
lated systolic hypert~on had incrwsed LV wall METHODS
thickness and mass without LV chamber 8) Study sample: In 1948, residents of Framingham,
largement, but men had LV dilation and incmased Massachusetts,who were between the ages of 28 and
LV mass without increased wall thickness. In cotk 62 were enrolled in a prospective epidemiologic study.
cludon, atthough isolated systolic hypertension The selection criteria and study design have been de-
was associated with increased LV mass in men scribed previously.7vsIn 1971, children of the original
and women, the geometric pattern of increased study population and the spousesof those children were
LV msss diffemd by sex; atthough women demoik enrolled in the Framingham Offspring Study.g From
stratedapattemofconce&khyp&mphy,anw 1979to 1983,membersof the original cohort underwent
centricpattemwasobservedinmen. their 16th examination and subjects in the Offspring
(Am J Cardiol1993;72:3lM3) Study underwent their secondexamination. Theseexam-
inations routinely included 1Zlead resting electrocar-
diography, measurementsof resting blood pressure,an-
thropometric measurements,determinations of blood
glucose levels, and M-mode echocardiography.
Subjects who attended the index examination and
who were 250 years old, took no antihypertensivemedi-
cation and with a diastolic blood pressure~90 mm Hg,
From the Framingham Heart Study, Framingham, Massachusetts;the and in whom LV masswas determinedby echccardiog-
National Heart, Lung, and Blood Institute, Bethesda,Maryland; and the raphy were included. Subjectswere excluded if they had
Cardiovascular Division and the Division of Clinical Epidemiology, any clinically apparent cardiovascular disease (conges-
Department of Medicine, Beth Israel Hospital, Harvard Medical tive heart failure, coronary artery diseaseor valvular dis-
School,Boston,Massachusetts.Manuscript received October 12,1992;
revised manuscriptreceived March 16, 1993,and acceptedMarch 18. ease).At each examination, evidence of cardiovascular
Address for reprints: Daniel Levy, MD, FraminghamHeart Study, disease was sought by medical history, physical ex-
5 Thurber Street,Framingham,Massachusetts01701. amination, 1Zlead electrocardiography,and review of

310 THE AMERICANJOURNALOF CARDIOLOGY VOLUME72 AUGUST1,1993


TABLE I Age and Age-Adjusted Characteristics of the Sample TABLE II Echocardiographic Measurements in Subjects with
NT
Isolated Systolic Hypertension and Normotensive Control
ISH
In = 538) (n = 26) Subjects
NT ISH
Men 1 (n = 538) (n = 26) p Value

Body mass index* (kg/m21


Systolic BP* (mm Hg)
Diastolic
Age (years)BP* (mm Hg)
26.4 ‘- 0.2
129.4 * 0.7
77.1 ft 0.3
60.2 0.3
26.8 f 0.7
172.3 f 2.6
82.7 2+ 1.3
66.9 1.3 1 LVM/height
LVID (mm)
SWT (mm)
RWT
(g/m) 113.1
49.5
20.0
0.41
+ 1.3
+ 0.2
f 0.1
Men

? 0.003
128.5
51.4
20.8
0.41
+
f
2
*
5.3
0.8
0.5
0.013
0.0055
0.03
0.16
0.83
n = 744 n = 53 FS (%I 36.9 zc 0.2 36.2 2 0.8 0.38

Age (years) 61.1 ? 0.3 71.7 r 1.2 Women


Body mass index* (kg/m*) 25.2 -t 0.2 25.5 f 0.6
Systolic BP* (mm Hg) 127.3 + 0.5 167.7 ? 1.9 n = 744 n = 53
Diastolic BP* (mm Hg) 74.3 f 0.3 80.9 k 1.0 LVM/height (g/m) 86.8 + 0.9 101.0 + 3.1 0.0001
;A$-%$sk?~a~.~~~es within sex (age groups < 65 yean and r 65 years). LVID (mm) 44.7 + 0.1 44.9 + 0.5 0.85
SWT (mm) 18.0 + 0.1 19.6 f 0.3 0.0001
BP = blood pressure; ISH = isolated systohc hypertension; NT = normotensive.
RWT 0.41 r 0.003 0.44 f ,010 0.0009
FS (%) 39.2 k 0.2 38.5 2 0.6 0.26
Values are mean + SEM, adjusted for age group, diastolic blood pressure, and b&y
hospital records. Medical records were routinely ob- mass index.
ISH = isolated systolic hypertension; LVID = left ventricular mternal dimension in
tained for participants who did not appearfor an exami- diastole; LVM = left ventricular mass: NT = normotensive; RWT = relative wall
nation and were evaluated for evidence of incident car- thickness; SWT = sum of ventricular septal and posterior wall thickness in diastole;
FS = fractional shortenlog.
diovascular disease.All suspectedcardiovasculardisease
events were reviewed by 3 physicians who evaluatedthe
pertinent records. Coronary artery disease events in- groups with and without isolated systolic hypertension
cluded angina pectoris, unstable angina, myocardial in- using multiple linear regression14J5to adjust for age, di-
farction, and sudden or nonsudden death attributed to astolic blood pressureand body mass index. The prev-
coronary artery disease.Criteria for the various cardio- alence of LV hypertrophy was comparedbetween those
vascular diseaseevents have been reported previously.1o with and without isolated systolic hypertension, first by
The echocardiogramwas not usedto determine the pres- &i-square analysis, followed by multiple logistic regres-
ence or absenceof cardiovasculardisease.Subjectswere sion to adjust for age, body mass index and diastolic
stratified by the presenceor absenceof isolated systolic blood pressure.14,r5Statistical significance was assessed
hypertension (delined as a systolic blood pressure2160 at p co.05 in each comparison.
mm Hg and a diastolic blood pressure~90 mm Hg” on
an average of 2 readings). RESULTS
Bc methods: The echocardiograph- Study sample: Of the 6,214subjects(2,803 men and
ic methodsused in this study have been describedprevi- 3,411 women) who attended the index examination,
ou~ly.~*Subjectswere studied with M-mode echocardi- 3,646 were 250 years old. Among these subjects, 665
ography. LV internal diameter and LV wall thickness were excluded due to preexisting cardiovasculardisease,
were measured at end-diastole, according to the meth- an additional 922 were taking antihypertensive medica-
ods of Devereux and Reichek (the Penn convention).13 tion and 268 had diastolic hypertension or incomplete
LV masswas calculated with the following formula: LV blood pressuredata. Echocardiogramsof adequatequal-
mass (grams)= 1.04 [(LV internal dimension + ven- ity to assessLV mass were obtained in 1,361 subjects
tricular septal thickness + posterior wall thickness)3- (564 men and 797 women). Subjectswith isolated sys-
(W internal dimension)3] - 13.6. To correct for differ- tolic hypertension were older (4 years in men and 8
encesin heart size in subjectsof different body size, LV years in women) and had higher diastolic blood pressure
mass (grams) was divided by height (meters), because readings (about 7 to 10 mm Hg) than normotensive pa-
of the associationobservedbetween LV massand height tients (Table I). Comparedwith subjectswho had echo-
in a previously detined healthy reference group of 864 cardiograms that could not be evaluated, subjects with
subjects.‘* Unless otherwise specified, all values report- adequateechocardiogramswere younger (60 vs 71 years
ed here for LV mass have been standardizedfor height. in men, and 62 vs 71 years in women) and less likely
LV hypertrophy was delined as a value of LV mas- to have isolated systolic hypertension (4.6% vs 7.5% in
s/height 22 SDS above the mean for the healthy refer- men, and 6.6% vs 11.1%in women).
ence group (143 g/m in men and 102 g/m in women).‘* -- -f-w
Fractional shortening was computed as the ratio of LV tdc hypertenskn (Ta#e II): Isolated systolic hyperten-
diastolic diameter-LV end-systolic diameter divided by sion was associated with higher values of LV mas-
LV diastolic diameter. s/height in men (p = 0.0055) and in women (p = 0.0001)
StatistI& analysis Separate analyses were per- in linear regression models adjusting for age, diastolic
formed for men and women. Mean values for LV mass blood pressure,and body massindex. The magnitude of
(standardized for height), LV internal dimension, the the increasedLV mass associatedwith isolated systolic
sum of ventricular septal and posterior wall thickness, hypertension was similar for both sexes: 15 g/m in men
and relative wall thickness were compared between and 14 g/m in women.

ISOLATED SYSTOLIC HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY 311


In men and women, isolated systolic hypertension trol subjectswho were not hypertensive and had no ev-
was associatedwith a higher prevalenceof LV hypertro- idence of cardiovascular diseaseby history or physical
phy than in normotensive subjects. The prevalence of examination. They found a significantly higher preva-
LV hypertrophy, comparing subjects with isolated sys- lence of LV hypertrophy in subjects with isolated sys-
tolic hypertension to normotensive subjects,was 31 ver- tolic hypertension (26% [22 of 841 vs 10% [5 of 511).
sus 12% (p = 0.005) in men and 57 versus 17% (p However, there was no adjustment in their analysis for
<o.OOOl)in women. Adjusting for diastolic blood pres- the lower diastolic blood pressurein normotensive sub-
sure and body mass index, the odds of LV hypertrophy jects compared with patients with isolated systolic hy-
was significantly greater in those with isolated systolic pertension, nor was adjustment made for the slightly
hypertension @ = 0.015 in men and p <O.OOOlin wom- higher body mass.
en). The relative odds of LV hypertrophy associatedwith Pearsonand colleagues’ also investigateddifferences
isolated systolic hypertension was 2.58 (95% conlidence in LV geometry that were responsible for the increased
interval [CT] 0.97 to 6.86) in men and 5.94 (95% CI prevalence of LV hypertrophy in subjectswith isolated
3.06 to 11.53)in women, after controlling for age, dia- systolic hypertension. They reported that subjects with
stolic blood pressure and body mass index using mul- isolated systolic hypertension had signilicantly greater
tiple logistic regression,After pooling the data for men wall thickness than did normotensive subjects, but no
and women, the relative odds of LV hypertrophy was significant differencesin LV end-diastolic or end-systol-
4.53 (95% CI 2.65 to 7.75), adjustedfor age, sex, body ic diameter were observed between the groups. That
mass index and diastolic blood pressure. study had approximately equal numbers of men and
The sum of LV septal and posterior wall thickness, women in each group, but analyseswere not performed
LV internal dimension, relative wall thickness, and frac- separatelyfor men and women.
tional shortening were compared between groups with Increasedrelative wall thickness in women has been
and without isolated systolic hypertension after adjust- noted in other settings. Hypertensive hypertrophic car-
ing for age, diastolic blood pressureand body mass in- diomyopathy of the elderly, a condition characterizedby
dex. In men, isolated systolic hypertension was associ- thick LV walls and a small LV cavity may be observed
ated with a signilicant increasein LV internal dimension more often in women.22Also, in a recent study of 34
(p = 0.03), but not the sum of the LV septal and poste- women and 29 men, aged 260 years who had aortic
rior wall thickness (p = 0.16) or relative wall thickness stenosis,Carroll et al6 found that, despite a similar de-
@ = 0.83). In women, isolated systolic hypertensionwas gree of LV outflow obstruction in men and women, the
associatedwith a significant increase in the sum of the women had a greater likelihood than men of having su-
LV septal and posterior wall thickness (p = 0.0001) and pernormal LV ejection performance and a small, thick-
relative wall thickness (p = 0.0009), but not in LV in- walled LV chamber.
ternal dimension (p = 0.85). Isolated systolic hyperten- Recently, a Framingham Heart Study report exam-
sion was associatedwith a greater increasein LV inter- ined blood pressurelevels over 30 years and found that
nal dimension in men than in women (p = 0.042), and a changes in LV mass associatedwith 30-year average
greater relative wall thickness in women than in men systolic blood pressure levels reflected changes in LV
(p = 0.018).Isolated systolic hypertension was not asso- wall thickness but not in LV internal dimension.23Our
ciated with any change in LV systolic function in men report complementsthe previous study by comparing LV
and women. mass and geometry in subjectswith and without isolat-
ed systolic hypertension. The 2 studies together suggest
DISCUSSION that although systolic blood pressureover the wide range
Isolated systolic hypertension and LV hypertrophy, of values is signilicantly associatedwith an increase in
common findings in elderly patients,16J7are associated relative wall thickness, at the extremesof systolic blood
with increasedrisk of cardiovascular and cerebrovascu- pressure that define isolated systolic hypertension, the
lar morbidity and mortality.18-21The associations be- associationwith an increasein relative wall thickness is
tween isolated systolic hypertension and LV mass and seen only in women.
geometry,however, have not been previously studied in There is no clear explanation for the differences in
a large population-based sample. Our principal finding the LV geometry between men and women, but there is
is that although isolated systolic hypertension, in a co- experimental and observational data that cardiac per-
hort free of clinically apparentcoronary heart disease,is formance and adaptation differ between men and wom-
associatedwith a similar increase of LV mass in men en. Capassoet al24 showed that the contractile perfor-
and women, the pattern of the increasedLV massis dif- mance of papillary muscles from male rats is different
ferent. Men with isolated systolic hypertension have a from female rats. Schaible and Scheuer25reported that
larger LV internal dimension without increasedLV wall intrinsic cardiac function is greater in male rats than fe-
thickness, whereas women with isolated systolic hyper- male rats. In rats, female hearts hypertrophy in response
tension have greaterLV wall thicknesswithout increased to conditioning by swimming, whereas male hearts do
LV cavity size. not.4 Sex hormones appearto influence the development
Our finding that isolated systolic hypertension is as- of LV hypertrophy. Castration of denervatedrats is re-
sociated with increased LV mass agrees with a recent ported to decreaseLV weight in male rats and increase
report from the Systolic Hypertension in the Elderly Pro- LV weight in female rats.5
ject (SHEP).’ In that report, Pearsonet al studied 104 Differences in cardiovascular physiology have also
participants in the SHEP study and 55 age-matchedcon- been noted betweenmale and female humans.There are
312 THE AMERICANJOURNALOF CARDIOLOGY VOLUME72 AUGUST1,1993
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ISOLATEDSYSTOLICHYPERTENSIONAND LEFTVENTRICULARHYPERTROPHY 313