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Am J Physiol Heart Circ Physiol 303: H315–H322, 2012.
First published June 1, 2012; doi:10.1152/ajpheart.00142.2012.
Effect of healthy aging on left ventricular relaxation and diastolic suction
Graeme Carrick-Ranson,1,2 Jeffrey L. Hastings,1,2,3 Paul S. Bhella,2 Shigeki Shibata,1,2 Naoki Fujimoto,1,2
M. Dean Palmer,2 Kara Boyd,2 and Benjamin D. Levine1,2
1
University of Texas Southwestern Medical Center at Dallas, 2Institute for Exercise and Environmental Medicine, Texas
Health Presbyterian Hospital Dallas, 3Veterans Affairs North Texas Health Care System, Dallas, Texas
Submitted 22 February 2012; accepted in final form 24 May 2012
aging; diastolic function; Doppler imaging; relaxation
rates increase sharply with advancing age (15). Because many adults over the age of 65 years
with heart failure have apparently preserved systolic function
(ejection fraction ⬎50%), diastolic dysfunction contributes
substantially to the heart failure syndrome in adults ⱖ65 yr
(seniors) (36, 42). Longitudinal measures of persistent or
worsening left ventricular (LV) diastolic function are predictive of new-onset heart failure (26). Thus, there is an emerging
need to comprehensively understand specific age-related
changes in LV diastolic filling to distinguish pathological from
healthy physiological variation.
With healthy aging, a slower peak early mitral annular
longitudinal velocity (Em), a prolonged isovolumic relaxation
time (IVRT), a slower early propagation velocity (VP), and a
reduction in intraventricular pressure gradient (IVPG), which
HEART FAILURE HOSPITALIZATION
Address for reprint requests and other correspondence: B. D. Levine,
Institute for Exercise and Environmental Medicine, 7232 Greenville Ave.,
Suite 435, Dallas, TX 75321 (e-mail: [email protected]).
http://www.ajpheart.org
is consistent with slowed active ventricular relaxation and
diastolic suction, have been reported previously (4, 19, 27, 34,
35). However, because Doppler parameters of diastolic filling
are influenced by changes in LV loading conditions in healthy
individuals (6, 7, 16, 35), it remains unclear to what extent
age-related changes result from alterations in intrinsic LV
properties and/or to cardiovascular loading conditions. Moreover, there is little information whether there is a concomitant
reduction in the responsiveness of LV filling properties to
alterations in LV filling pressure [pulmonary capillary wedge
pressure (PCWP)] with advancing age. Such information is
important to establish whether slowed relaxation and diastolic
suction may compromise LV filling in seniors during conditions in which rapid changes in LV volume are required such
as exercise or orthostatic stress.
Accordingly, the aims of this study were to determine: 1) at
what stage of life are active relaxation and diastolic suction
slowed with healthy aging and 2) whether the response of LV
relaxation and diastolic suction properties to alterations in
PCWP is reduced with healthy aging. To achieve these aims,
Doppler measures of LV diastolic filling, LV end-diastolic
volume (LVEDV), and hemodynamics were collected over a
range of LV filling pressures in healthy individuals aged 21–77
yr at specifically defined stages of aging.
METHODS
Participant Characteristics
Subjects were recruited from the Dallas Heart Study, a populationbased probability sample of ⬇6,100 individuals in the Dallas-Fort
Worth metroplex who have been carefully screened with a detailed
history, clinical exam, and selected diagnostic tests as previously
described (43). To enrich the total sample, subjects were additionally
recruited from a random sample of ⬇20,000 employees at Texas
Health Resources, the third largest employer in the Dallas-Fort Worth
metroplex and a diverse health care company. All subjects were
nonsmokers, were not taking any cardiovascular medications, had a
24-h blood pressure ⬍140/90 mmHg, body mass index ⱕ30 kg/m2,
and had a normal electrocardiogram and exercise stress echocardiogram. Subjects were either sedentary or casual exercisers with all
subjects exercising no more (and usually less than) than three times
per week on a regular basis.
All study procedures were approved by the Institutional Review
Boards of the University of Texas Southwestern Medical Center at
Dallas and Presbyterian Hospital, and all subjects signed an informed
consent form.
Cardiovascular Assessment
LV function was assessed using previously described techniques
(1, 35). Briefly, a 6-Fr balloon-tipped fluid-filled catheter (Edwards
Lifesciences) was placed using fluoroscopic guidance through an
antecubital vein in the pulmonary artery. The catheter was connected to a pressure transducer with the zero reference point set 5.0
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Carrick-Ranson G, Hastings JL, Bhella PS, Shibata S, Fujimoto N, Palmer MD, Boyd K, Levine BD. Effect of healthy aging
on left ventricular relaxation and diastolic suction. Am J Physiol Heart
Circ Physiol 303: H315–H322, 2012. First published June 1, 2012;
doi:10.1152/ajpheart.00142.2012.—Doppler ultrasound measures of
left ventricular (LV) active relaxation and diastolic suction are slowed
with healthy aging. It is unclear to what extent these changes are
related to alterations in intrinsic LV properties and/or cardiovascular
loading conditions. Seventy carefully screened individuals (38 female,
32 male) aged 21–77 were recruited into four age groups (young:
⬍35; early middle age: 35– 49; late middle age: 50 – 64 and seniors:
ⱖ65 yr). Pulmonary capillary wedge pressure (PCWP), stroke volume, LV end-diastolic volume, and Doppler measures of LV diastolic
filling were collected at multiple loading conditions, including supine
baseline, lower body negative pressure to reduce LV filling, and saline
infusion to increase LV filling. LV mass, supine PCWP, and heart rate
were not affected significantly by aging. Measures of LV relaxation,
including isovolumic relaxation time and the time constant of isovolumic pressure decay increased progressively, whereas peak early mitral
annular longitudinal velocity decreased with advancing age (P ⬍
0.001). The propagation velocity of early mitral inflow, a noninvasive
measure of LV suction, decreased with aging with the greatest
reduction in seniors (P ⬍ 0.001). Age-related differences in LV
relaxation and diastolic suction were not attenuated significantly when
PCWP was increased in older subjects or reduced in the younger
subjects. There is an early slowing of LV relaxation and diastolic
suction beginning in early middle age, with the greatest reduction
observed in seniors. Because age-related differences in LV dynamic
diastolic filling parameters were not diminished significantly with
significant changes in LV loading conditions, a decline in ventricular
relaxation is likely responsible for the alterations in LV diastolic
filling with senescence.
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LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
Echocardiography Assessment
Echocardiographic images were digitally acquired using an iE33
(Philips) and ATL HDI5000 (Advanced Technology Laboratories,
Bothell, WA) and were measured offline in an Xcelera cardiovascular image management system (Philips). LV volumes were
determined using a modified Simpson’s method as previously
described (1). Because LV volumes by echocardiography have
been reported to underestimate those by magnetic resonance imaging (MRI) (24), a correction factor was determined as the ratio
of LVEDV by echocardiography at baseline 1 to that by cardiac
MRI in each subject. This individual correction factor was used to
correct LV volumes by echocardiography during loading and
unloading conditions to eliminate errors due to foreshortening or
suboptimal echo images.
Diastolic filling. A 2-mm sample volume placed at the tips of the
mitral valve leaflets was used to determine peak velocities of mitral
inflow.
Tissue Doppler imaging. In the apical four-chamber view, a 2-mm
sample volume was placed at the septal and lateral side of the mitral
annulus. Septal and lateral values were averaged to obtain a mean
tissue Doppler imaging value (29, 35).
Vp of early mitral inflow. A color M-mode image of LV inflow was
obtained with the sampling area positioned to extend from midatrium
to the apex, directly through the mitral valve orifice. The scale was
reduced to produce a clear aliasing within the early portion of the
mitral inflow. The slope of first aliasing velocity from the mitral plane
to 4 cm into the ventricle was used to measure VP (18). With the use
of a five-chamber apical view with a 4-mm sample volume, the interval between aortic valve closing and mitral valve opening (IVRT)
was determined.
Time constant of isovolumic pressure decay. The time constant of
isovolumic pressure decay with zero asymptote assumption (␶) was
calculated by the following formula (34, 37):
␶共ms兲 ⫽
IVRT
ln共P兲 ⫺ ln共PCWP兲
where P is systolic blood pressure and PCWP is mean PCWP. All
parameters were collected at end-expiration, and at least three measurements were averaged.
Global systolic function. Global systolic function was assessed by
1) peak systolic mitral annular velocity (Sm); 2) the ejection fraction;
and 3) the end-systolic blood pressure/end-systolic volume index
(ESBP/ESVI) relationship, where ESBP was estimated as brachial
systolic pressure ⫻ 0.9 (10).
Statistical Analysis
Baseline 1 was used for group comparisons of supine resting measures. A one-way ANOVA was used to test the effect of age on group
subject characteristics, resting hemodynamics, and Doppler measures. A
repeated-measures two-factor ANOVA (age, condition) was used to
determine the effect of aging on Doppler parameters during LV loading
and unloading. To determine whether there is a reduction in the responsiveness of LV relaxation and diastolic suction properties to alterations in
PCWP with advancing age, an ANOVA was conducted on the delta
change (%) in LVEDV index and Doppler filling parameters from
baseline 1 to LBNP ⫺15 mmHg (LBNP15), and from baseline 2 to saline
infusion of 10 –15 ml/kg (NS15). Tukey adjustments were used to control
for multiple comparisons. Nonparametric data were analyzed via
Kruskal-Wallis ANOVA on ranks. P ⬍ 0.05 was considered statistically
significant. All statistical analysis was performed using SigmaStat (Systat
Software) and SAS version 9.1 (SAS Institute). Data are presented as
means ⫾ SD in Tables 1 and 2 and means ⫾ SE in Figs. 1–3.
RESULTS
Participant Characteristics and Baseline Global
LV Hemodynamics
There were no significant age-related changes in total body
mass or BSA (Table 1). As a result of a larger SVI and an
increased heart rate, QI was greater in the young group compared with the other groups (Table 2). Blood pressures were
increased in seniors compared with the younger groups
(ANOVA age effect, P ⬍ 0.001). Whereas indexed EDVI and
ESVI were smaller, ejection fraction increased with aging and
was greatest in seniors (ANOVA age effect, P ⬍ 0.001) (Table
1). Because of a smaller ESVI and a greater ESBP, ESBP/
ESVI (mmHg·ml⫺1·m⫺2) was greatest in the seniors (ANOVA
age effect, P ⬍ 0.001); however, Sm, a measure of longitudinal
shortening during systole, declined with age (P ⬍ 0.001).
Likewise, SVR increased with aging (ANOVA age effect, P ⬍
0.001). LV mass index, PCWP, RAP, and LVTMP did not
differ significantly among age groups (Table 2).
Baseline Doppler Echocardiography
The peak of the E wave declined 20% from the young group
until late middle age, and then plateaued (ANOVA age effect,
P ⬍ 0.001) (Fig. 1B). The E/A ratio declined in a linear trend from
Table 1. Participant characteristics
Subjects (n, % female)
Age, yr
Weight, kg
BSA, m2
Young
Early Middle Age
Late Middle Age
Seniors
ANOVA P Value
14 (43)
28 ⫾ 4
69 ⫾ 9
1.80 ⫾ 0.14
19 (68)
42 ⫾ 5*
68 ⫾ 14
1.77 ⫾ 0.22
23 (52)
57 ⫾ 4*
77 ⫾ 14
1.90 ⫾ 0.21
14 (50)
70 ⫾ 3*
73 ⫾ 10
1.85 ⫾ 0.17
⬍0.001
0.105
0.163
Values presented are means ⫾ SD. BSA, body surface area. *P ⬍ 0.05 vs. young group.
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cm below the sternal angle. Resting supine measures (baseline 1)
were collected, and then LV filling was decreased using lower
body negative pressure (LBNP) of ⫺15 mmHg (LBNP15). Mean
PCWP (as an index of mean LA pressure) and Doppler measurements were collected after 5 min of LBNP. After release of LBNP
and confirmed return to hemodynamic baseline (baseline 2), defined by ⱕ10% difference in stroke volume from baseline 1
(coefficient of variation, 7.9%), LV filling was then increased
through a rapid infusion of warm (37°C) isotonic saline solution at
200 ml/min to achieve total volume infusion of 10 –15 ml/kg
(NS15). Irrespective of age, we observed a 2- to 3-mmHg mean
difference in PCWP between baseline 1 and baseline 2, which may
influence Doppler measures. Accordingly, baseline 1 and 2 were
treated as two separate loading conditions. LV end-diastolic transmural filling pressure (LVTMP) was calculated as PCWP ⫺ right
atrial pressure (RAP) as previously described (17).
Cardiac output (Qc) was measured with the acetylene rebreathing
method (41), which has been previously validated in this laboratory
(23). Qc and stroke volume were indexed to body surface area (BSA)
(QI and SVI, respectively). Systemic vascular resistance (SVR) was
calculated by the following formula: SVR ⫽ MAP/Qc ⫻ 80, where
MAP is mean arterial pressure and 80 is a conversion factor to dynes
per second per centimeter to the fifth power.
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LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
Table 2. Left ventricular hemodynamics and volumes
2
Early Middle Age
Late Middle Age
Seniors
ANOVA P Value
3.3 ⫾ 0.8*
73 ⫾ 14
47 ⫾ 9
113 ⫾ 11
64 ⫾ 7
81 ⫾ 7
1,131 ⫾ 291
66 ⫾ 7
24 ⫾ 4
64 ⫾ 5
4⫾1
10 ⫾ 2
54 ⫾ 7
12.6 ⫾ 1.3
9.1 ⫾ 1.6
3.4 ⫾ 0.8
2.6 ⫾ 0.5*
68 ⫾ 9
38 ⫾ 6*
110 ⫾ 3
71 ⫾ 12
84 ⫾ 11
1,541 ⫾ 400*
62 ⫾ 10
21 ⫾ 7
67 ⫾ 7
5⫾2
9 ⫾ 1*
54 ⫾ 13
11.9 ⫾ 2.6
8.6 ⫾ 1.9
3.4 ⫾ 1.2
2.6 ⫾ 0.4*
64 ⫾ 8
41 ⫾ 7
113 ⫾ 4
72 ⫾ 7
86 ⫾ 8
1,438 ⫾ 237*
60 ⫾ 9
17 ⫾ 5*
72 ⫾ 6*
7 ⫾ 2*
8 ⫾ 1#
50 ⫾ 8
11.9 ⫾ 2.4
8.8 ⫾ 1.8
3.1 ⫾ 1.3
2.6 ⫾ 0.3*
71 ⫾ 10
38 ⫾ 9*
134 ⫾ 4*
78 ⫾ 9*
96 ⫾ 11*
1,617 ⫾ 263*
50 ⫾ 7*
14 ⫾ 3*
73 ⫾ 4*
9 ⫾ 2*
8 ⫾ 1#
48 ⫾ 7
11.3 ⫾ 1.2
7.8 ⫾ 1.6
3.5 ⫾ 1.5
⬍0.001
0.058
0.008
⬍0.001
0.003
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
0.034
0.228
0.472
0.216
0.802
Values presented are means ⫾ SD. QI, cardiac index; SVI, stroke volume index; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean
arterial pressure; SVR, systemic vascular resistance; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; ESBP, end-systolic blood pressure;
Sm, peak systolic mitral annular velocity; LVMI, left ventricular mass index; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; LVTMP,
left ventricular transmural pressure. Left ventricular mass, left ventricular end-systolic volume index, and ejection fraction were determined using magnetic
resonance imaging as previously described (1). *P ⬍ 0.05 and #P ⫽ 0.051– 0.055 vs. young group.
2.0 in the young group to below 1.0 (0.9 ⫾ 0.2) in the seniors
(ANOVA age effect, P ⬍ 0.001) (Fig. 1A). Em slowed (⬇1
cm/decade) while IVRT increased 57% from the young group
(91 ⫾ 17 ms) to the seniors (144 ⫾ 28 ms), resulting in an overall
aging effect for both measures (P ⬍ 0.001) (Fig. 1, C and D). The
relationship between advancing age and slowed relaxation was
supported by a progressive slowing (⬇3.5 ms/decade) in ␶, increasing 40% from the youngest to oldest group (42 ⫾ 9 to 59 ⫾
11 ms) (ANOVA age effect, P ⬍ 0.001) (Fig. 1E). There was an
early decline in VP from 55 ⫾ 7 cm/s in the young group to 46 ⫾ 6
cm/s in the early middle age group. VP then plateaued during late
middle age, and then declined further in the seniors. Overall, there
was a 35% decline in VP from the youngest to oldest group (Fig. 1F).
Influence of LV PCWP
The relative changes in PCWP from baseline 1 to LBNP15
and baseline 2 to NS15 were not significantly different be-
Fig. 1. The effect of healthy aging on the E/A ratio (A), E (B), peak early mitral annular longitudinal velocity (Em, C), isovolumic relaxation time (IVRT, D),
the time constant of isovolumic pressure decay with zero asymptote assumption (␶, E), and propagation velocity (VP, F). Boxes represent group means. *P ⬍
0.05 and #P ⬍ 0.070 – 0.076 vs. young group.
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QI, l/m
Heart rate, beats/min
SVI, ml/m2
SBP, mmHg
DBP, mmHg
MAP, mmHg
SVR, dynes · s⫺1 · cm5
EDVI, ml/m2
ESVI, ml/m2
Ejection fraction, %
ESBP/ESVI, mmHg · ml⫺1 · m⫺2
Sm, cm/s
LVMI, g/m2
PCWP, mmHg
RAP, mmHg
LVTMP, mmHg
Young
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LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
dent, with the relative change in response to loading and
unloading being unaffected by age (P ⫽ 0.339 and 0.847,
respectively). Nevertheless, the Em of the late middle age and
seniors groups failed to reach baseline levels of those in the
early middle age and young groups despite PCWP being
increased ⬇75– 80% (Fig. 3B). IVRT decreased in seniors
from 135 ⫾ 27 to 106 ⫾ 26 ms (P ⬍ 0.001) with LV loading,
suggesting earlier mitral value opening. However, the change
in IVRT in response to an increased volume load was not
significantly influenced by aging (P ⫽ 0.537); thus, IVRT
remained slower in seniors compared with the two youngest
groups (P ⫽ 0.004 compared with the young group and P ⫽
0.007 compared with the early middle age group) (Fig. 3C).
Although the relative decrease in VP during LV unloading was
less prominent in seniors, VP still remained slower compared
with all other groups (Fig. 3D). The increase in VP in response
to increased LV load increased with aging (P ⫽ 0.018);
Fig. 2. The effect of aging on left ventricular (LV) volumes: stroke volume index (SVI, A) was smaller in the seniors compared with the youngest group during
baseline, whereas end-diastolic volume index (EDVI) was considerably smaller in the seniors during unloading and loading compared with all other age groups
irrespective of whether pulmonary capillary wedge pressure (PCWP) or LV end-diastolic transmural filling pressure is used (B and C). Note the scale change
used for B and C. LBNP15, lower body negative pressure of ⫺15 mmHg; NS15, isotonic saline solution at 200 ml/min to achieve total volume infusion of 10 –15
ml/kg. *P ⬍ 0.05 vs. young group at the same loading condition. Values are means ⫾ SE.
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tween age groups (P ⫽ 0.076 and 0.233). The relative change
(%) in SVI to LBNP was smallest in the seniors and largest in
the young group (P ⫽ 0.052), but was similar between groups
in response to saline infusion (P ⫽ 0.287). As a result, SVI
remained larger in the young group compared with the other
age groups at any given PCWP (Fig. 2A). The change in EDVI
during unloading or loading conditions was not age dependent
(P ⫽ 0.899 and 0.906, respectively). As a result, EDVI remained smaller in the oldest group during these conditions
compared with the younger age groups (Fig. 2B), an effect that
was preserved relative to LVTMP (Fig. 2C). As expected, the
E/A ratio varied directly and predictably in response to changes
in PCWP, decreasing with LV unloading and increasing with
loading in similar proportions in all groups (Fig. 3A). Thus,
while seniors achieved an E/A ratio over one with LV loading,
this value remained lower compared with the younger subjects
during all conditions. Likewise, Em was very preload depen-
LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
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however, VP still remained slower in seniors compared with all
other groups (pⱕ0.001).
DISCUSSION
The key finding of this study is a progressive slowing of LV
relaxation beginning in early middle age, with a significant
concomitant reduction in ventricular diastolic suction in those
ⱖ65 yr. Because these differences among age groups occur
despite a similar LV filling pressure, heart rate, and mass, and
remained during large changes in cardiac loading conditions,
we interpret these findings to suggest that intrinsic ventricular
properties are primarily responsible for the age-related changes
in diastolic filling with advancing age. A marked reduction of
relaxation and diastolic suction in healthy seniors is particularly relevant given the emergence of diastolic dysfunction as
an important determinant of heart failure in seniors (36, 42).
Although there is a plethora of studies investigating the
effect of healthy aging on Doppler measures of LV function,
very few studies have collected Doppler measures over a
wide range of LV filling pressures in healthy subjects
varying in age (35). Given that Doppler measures are
load-dependent in healthy individuals (11, 16), it is therefore very difficult to determine from previous findings
whether age-related alterations in LV diastolic filling are
related to changes in intrinsic ventricular properties and/or
differences in LV loading conditions, in particular left atrial
and ventricular pressures. To address this limitation, we
collected multiple measures of LV dynamic diastolic filling
over a wide range of PCWP (2.8 –20.3 mmHg) in a large
cohort of healthy individuals over a broad age range. This
current study demonstrated that neither an increase in
PCWP in the older subjects nor a reduction in PCWP in the
younger subjects was sufficient to change fundamental agerelated differences in LV diastolic filling parameters. Therefore, a deterioration in baseline levels of LV relaxation and
diastolic suction resulting from changes in intrinsic ventric-
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Fig. 3. The effect of aging and changes in PCWP on Doppler measures of LV diastolic filling. A: the E/A ratio varied in relation to PCWP (loading condition
main effect, P ⬍ 0.001) but remained lower in the late middle age and seniors compared with the young group during all conditions (age main effect, P ⬍ 0.001).
B: Em was altered in response to changes in PCWP (loading condition main effect, P ⬍ 0.001). Across all loading conditions, Em was faster in the young group
compared with all other groups. Em of the two older groups did not reach baseline levels of the younger groups even when PCWP was increased (age main effect,
P ⬍ 0.001). C: IVRT was slower in the seniors vs. all other groups irrespective of loading conditions. D: while age-associated differences in baseline VP were
attenuated in the middle age groups during loading, the seniors group had an attenuated VP response, and consequently remained lower compared with the other
groups across all LV filling pressures (age ⫻ loading condition interaction effect, P ⬍ 0.001). *P ⬍ 0.05 vs. young group at the same loading condition. Values
are means ⫾ SE.
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LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
ular function seems to be the most prominent effect of aging
on dynamic LV diastolic filling.
Slowed LV Active Relaxation With Healthy Aging
Methodological Limitations
There are several limitations to this current study. First, the
number of subjects was relatively small in each age group,
primarily as a result of the invasive experimentation nature of
this study. We chose to investigate age-related differences
derived from predetermined age groups based on important
physiological aging milestones. This approach increases statistical power to detect group differences but comes at the
expense of age resolution. Therefore, the current results do not
imply that there is a sudden and dramatic change in Doppler
measures as a person advances from age 64 to age 65, but
rather emphasize that, as men and women advance through the
stages of life, there are real and measureable alterations in
Doppler measures of LV diastolic filling. Second, whereas the
collection of LV end-diastolic pressure would allow for the
direct determination of the transmitral pressure gradient, given
that PCWP could be used as a surrogate for left atrial pressure,
the advantage of a left heart catheter for the measurement of
LV pressures did not outweigh the risk for these experiments in
our healthy volunteers. Finally, although not presented within
this current manuscript, more novel and sensitive echocardiography techniques (twist and untwisting) may provide more
detailed analysis of age-related changes in LV diastolic filling
associated with healthy aging, particularly during perturbations
in LV filling conditions (i.e., exercise, tilt table, LBNP).
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This current study showed that Em, IVRT, and ␶ were
slowed in a linear fashion with advancing age, even in the
absence of manifest comorbid conditions such as hypertension,
coronary artery disease, or obesity. Likewise, in 1,333 subjects
aged from 10 – 89 (mean age 55 yr) with no known heart
disease, Em declined progressively with advancing age (33),
whereas IVRT is prolonged in older vs. younger adults (22,
44). Because these measures represent early active relaxation,
these findings are consistent with the hypothesis of slowed
ventricular active relaxation with aging.
This current study demonstrated that these measures were
not restored to youthful levels even when PCWP was significantly increased in those over the age of 50 yr. Thus, these
age-related changes in LV active relaxation are unlikely to be
related to loading conditions, but rather intrinsic LV relaxation
properties. Diastolic relaxation is heavily dependent on Ca2⫹
reuptake by sarcoplasmic reticulum (5). Biochemical studies in
rodents have demonstrated a reduction in intracellular Ca2⫹
clearance with aging (30, 40). The etiology for the decline in
intracellular Ca2⫹sequestration is not fully understood but is
most likely to be multifactorial, including decreased levels of
sarcoplasmic reticulum Ca2⫹-ATPase (SERCA) mRNA and
protein (9, 38), as well an overexpression and/or reduction in
phosphorylation of phospholamban (25, 28). The relative importance of Ca2⫹-regulating proteins such as SERCA on
slowed LV relaxation with aging is demonstrated by more
youthful levels of ␶ and ⫺dP/dt in aged rodent hearts with
adenoviral transfer of the SERCA gene (38).
Diastolic suction results from the development of restoring
forces created in part by contraction below the equilibrium
volume (the volume when transmural pressure ⫽ 0 mmHg) and
the complex three-dimensional twisting deformation of the
myocardium during systole (3, 31, 32). This stored energy is
released during the subsequent diastolic period and contributes
to the generation of an IVPG, a regional pressure difference
within the ventricle (14) that acts as a suction force drawing
blood from the base to the apex. Recent studies show that
IVPGs can be estimated noninvasively using color M-mode
Doppler (20), and the magnitude of IVPGs is reduced in
seniors compared with younger healthy adults over a wide
range of LV filling pressures (34), which is consistent with the
current VP results. While it is acknowledged that VP is not a
direct measure of IVPGs, these findings are not surprising
given that VP is influenced by several physiological factors that
would also impact IVPGs (global systolic function, rapid
active relaxation, LV minimal diastolic pressure, and ventricular geometry) (2, 8, 39).
Whereas these current findings underscore the effect that LV
relaxation and diastolic suction may exert on Doppler measures
with aging, the influence of alterations in LV compliance with
age requires mention. We have recently reported in this same
cohort that there is LV atrophy and stiffening from early
middle age onward, with the greatest effects being observed in
seniors (17). We speculate that ventricular stiffening with
aging results from alterations in myocardial tissue, including
an increased volume fraction, cross-linking of collagen (ad-
vanced glycation end-products), and the accumulation of interstitial fibrosis, which have been discussed in detail elsewhere (17). However, given that the ventricle is likely to be
relatively compliant during early mitral inflow, it is unlikely
that overall ventricular stiffness exerts a meaningful effect
during this period of diastole. It is more likely that the impact
of ventricular stiffness is exerted later in the diastolic filling
period, when LV filling volumes and pressure are increased.
Although the clinical relevance of a reduction of ventricular
diastolic suction and prolonged relaxation with senescence has
not been fully elucidated, it could compromise LV filling
during conditions in which diastolic filling duration is shortened significantly, such as during exercise tachycardia. Mathematical models and experimental animal models have shown
that slowed active relaxation and less vigorous diastolic suction
during exercise tachycardia are associated with a significant
increase in left atrial filling pressure (12, 13, 21), which, if
excessive, may result in breathlessness and limit exercise
performance. However, to date, no studies have simultaneously
assessed LV filling pressures and diastolic filling during exercise in a large cohort of subjects of various ages; therefore, this
hypothesis remains purely speculative.
One recent longitudinal study in a large cohort of community-dwelling late middle age subjects and seniors reported that
persistent or worsening LV diastolic filling over the 4-yr period
resulted in an increased risk of new-onset heart failure during
a subsequent 6-yr follow up (26). Not surprisingly, being 65 yr
or older was predictive of the development of LV diastolic
dysfunction. Therefore, the findings of this current study may
provide greater understanding of specific age-related changes
in sedentary but healthy aging adults with normal LV filling
pressures. Such information may be useful for advancing the
current knowledge of what may constitute “age-appropriate”
changes in LV diastolic filling in seniors.
LEFT VENTRICULAR RELAXATION PROPERTIES WITH AGING
In summary, this current study demonstrated a slowing of
LV relaxation that begins in early middle age with sedentary,
but otherwise healthy, aging. Diastolic suction seems to be
relatively well preserved until 65 yr, but there is a clear
deterioration thereafter. These age-related changes occur despite a similar LV mass, PCWP, and heart rate, further demonstrating the reduction in intrinsic properties of relaxation and
diastolic suction with senescence.
GRANTS
This study was supported by National Institute on Aging Grant AG-17479-02.
DISCLOSURES
There are no author conflicts to disclose.
Author contributions: G.C.C.-R., J.L.H., P.S.B., S.S., N.F., M.D.P., K.B.,
and B.D.L. performed experiments; G.C.C.-R. analyzed data; G.C.C.-R.,
J.L.H., P.S.B., S.S., N.F., and B.D.L. interpreted results of experiments;
G.C.C.-R. prepared figures; G.C.C.-R. drafted manuscript; G.C.C.-R. and
B.D.L. edited and revised manuscript; J.L.H., P.S.B., and B.D.L. conception
and design of research; B.D.L. approved final version of manuscript.
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