Editorial
The Aging Human Heart
João A.C. Lima, MD
T here seems to be more about aging than living longer.1,2
Certainly, among most humans, longevity is determined
by exposure to environmental risk factors that account for
morbidity and eventual mortality.3 However, it is not known
whether control for most or all environmental risk factors
would assure humans unlimited survival. The concept that
among members of our species, survival is predetermined bio-
logically remains to be disproven.4 Worldwide, cardiovascular
risk factors remain the most important in limiting human sur-
vival and burdening human life.5 At the center of the cardio-
vascular system, how the heart remodels throughout human
Downloaded from http://circimaging.ahajournals.org/ by guest on May 1, 2018
life is, therefore, of particular importance to our understand-
ing of cardiovascular aging.
See Article by Hung et al
The advent of noninvasive technologies that allowed for
the direct assessment of global systolic function in humans led
to the important realization that, contrary to what one might
intuitively expect, left ventricular (LV) ejection fraction did
not decline with aging, particularly when obstructive coronary
artery disease was excluded or accounted for in longitudinal
cohorts.6 More recent work indicated in fact that the human
heart remodels significantly with aging,7 while the LV ejection
fraction remains at normal levels. The mechanisms of age-
related cardiac remodeling remain incompletely understood,
but how and why the aging heart remodels the way it does is
of great importance to gaining greater insight into cardiovas-
cular aging.
In this issue of Circulation: Cardiovascular Imaging, Hung
et al8 document important findings on human cardiac aging.
They demonstrate that advanced aging is associated with
greater LV concentricity expressed as the ratio of LV mass to
volume at end diastole, impaired relaxation with reduced fill-
ing, impaired longitudinal deformation with preserved circum-
ferential shortening, and greater torque, that is, shear in the
longitudinal–circumferential plane. Importantly, they also show
that this pattern of age-related remodeling is more pronounced
in women than in men, although with less myocardial shorten-
ing in men across all age groups in both the longitudinal and
circumferential orientations. According to such construct, and
as also proposed by previous work,9 concentric remodeling with
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Division of Cardiology, Department of Medicine, Johns
Hopkins Hospital and School of Medicine, Baltimore, MD.
Correspondence to João A.C. Lima, MD, Johns Hopkins Hospital, 600
N Wolfe St, Blalock 524, Baltimore, MD 21287. E-mail jlima@jhmi.edu
(Circ Cardiovasc Imaging. 2017;10:e005899.
DOI: 10.1161/CIRCIMAGING.116.005899.)
© 2017 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at
http://circimaging.ahajournals.org
DOI: 10.1161/CIRCIMAGING.116.005899
1
enhanced torque seems to compensate for contractile impair-
ment and such mechanisms being more pronounced among
women than men. Still, according with this line of thinking,
ejection fraction is maintained and sometimes even outstrips
the normal range in the aging heart, particularly among women.
Finally, the work of Hung et al8 is also remarkable from a meth-
odological standpoint because the findings are documented
by both 2-dimensional (2D) but particularly by 3-dimensional
(3D) echocardiography, opening the possibility of a much more
detailed analysis of cardiac mechanics in populations than those
afforded by 2D10 or Mmode11 echocardiography.
Torque was first reported by seventeenth century physi-
ologists who conceived cardiac function as similar to the
wringing of a wet towel through rotational forces applied in
opposing directions.12,13 It was later quantified as shear in the
longitudinal–circumferential plane by placement of implanted
markers14 and magnetic resonance imaging tagging.15 Its role
as a potential compensatory mechanism is suggested by the
plots in Figure 1F, showing the increase in the ratio of torque
to circumferential strain with aging by Hung et al.8 The work
also suggests a greater effect of aging on longitudinal than on
circumferential shortening and points to previous work sug-
gesting that longitudinal shortening is of greater importance
to LV ejection function than shortening in the circumferential
orientation.16 Conversely, it is possible that deformation in the
circumferential–radial plane is so essential to LV function that
remains preserved by torque and other mechanisms in the face
of longitudinal shortening impairment. Along a similar line
of thinking, it is conceivable that systolic function expressed
by LV ejection fraction or myocardial systolic strain indices
would be altered only at more advanced stages of subclinical
involvement. However, diastolic function might be impaired
earlier in a disease progression continuum since it is not as piv-
otal as systolic function. Conversely, among the limitations of
such type of thinking is the impressive reduction of stroke vol-
ume documented by this and previous work in association with
concentric remodeling and diastolic dysfunction. This could
reflect independent pathways of cardiovascular impairment
because of systolic versus diastolic dysfunction, which could
be sex related.8,9 Finally, from a mechanical standpoint, the
work by Hung et al8 reminds us once again of the limitations of
ejection fraction as an index of LV function across the human
lifetime. Recent work points to the advantages of integrating
structure and function to better express the effects of continued
risk factor exposure over prolonged periods of time.17
The main limitation of the work by Hung et al8 is acknowl-
edged by the authors and relates to the study design which
derives longitudinal inferences from cross- sectional relation-
ships obtained from the ARIC study (Atherosclerosis Risk in
Communities). Although the importance of cohort effects can-
not be underestimated, in the case of this specific study, at least
3 of the main parameters have been studied in longitudinal
 2  Lima  Aging Human Heart
studies involving individuals of similar age range enrolled in
MESA (Multiethnic Study of Atherosclerosis), in analyses
that also excluded participants with prevalent heart failure,
providing, therefore, a frame for comparison with the results
reported by Hung et al.8 As previously reported by Eng et al,18
LV mass increased in men but not in women over a period of
10 years but only by a small amount of in average 3 to 6 g.
By contrast, LV end-diastolic volume decreased both in men
and in women, and concentric remodeling expressed as the LV
mass to volume ratio increased markedly with aging. Based
on those results, findings of increased concentric remodeling
reported by Hung et al8 seem to be well supported by mag-
netic resonance imaging–determined LV mass and volume
measurements performed longitudinally. Similarly, longitudi-
nal measurements of circumferential shortening performed in
MESA using magnetic resonance imaging tagging19 support
the findings of Hung et al8 in ARIC using echocardiography.
The mechanisms underlying the age-related remodeling
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reported by Hung et al8 and others7,9,18,19 remain incompletely
understood. Age-related LV hypertrophy, now thought to be
primarily concentric, seems to be in part secondary to pro-
gressive systolic and pulse pressure increases combined with
diastolic blood pressure reduction.9 These cardiac remod-
eling alterations are in part attributed to increased arterial
stiffness associated with the aforementioned blood pressure
changes, as well as changes in body mass and composition
that also accompany human aging in industrialized societ-
ies. Numerous other factors underlie myocyte hypertrophy
due mostly to in series sarcomere growth as the heart ages,
and its susceptibility to sex hormonal modulation has been
proposed as one of the main mechanism of sex differences
in age-related LV remodeling and myocardial dysfunc-
tion20,21 as discussed by Hung et al.8 A myriad of additional
factors have been reported in association with cardiac aging
and several have been postulated as primary or contributing
determinants of cardiac remodeling, including age-related
apoptosis,22,23 metabolic dysregulation associated with
activation of the renin–angiotensin system,24 chronotropic
alterations related to aging of the autonomic nervous sys-
tem,25,26 mitochondrial abnormalities,27 and many others.28
Among them, the potential influence of myocardial fibrosis
has received particular attention,29 given that fibrosis plays a
pivotal role in vascular aging.30
Myocardial replacement fibrosis with scar formation is
primarily secondary to coronary artery disease and hyperten-
sive heart disease in population studies.31 It is more common
in men than in women and associated with LV dilatation and
eccentric remodeling in those studies.32,33 Conversely, intersti-
tial fibrosis is more common in women in population studies
and also associated with LV hypertrophy but not with specific
markers of coronary artery disease, such as coronary calcifica-
tion defined by computed tomography.34 Venkatesh et al35 have
reported the association of interstitial fibrosis with LV size
reduction, a central component of the aging-related concentric
remodeling reported here by Hung et al8 and by prior work.7
Moreover, Donekal et al32 reported associations of interstitial
fibrosis with both diastolic dysfunction and increased torque
among women and between interstitial fibrosis and regional
systolic dysfunction among women and men even after
participants with replacement fibrosis were excluded from the
analysis.
Taken together, such findings suggest a potential role for
myocardial interstitial fibrosis as a mechanism for alterations
reported by Hung et al.8
Finally, Hung et al8 demonstrate the feasibility of using 3D
echocardiography in over a thousand participants of a large
population study to study myocardial mechanics, in addition
to global indices of myocardial structure and function, such
as LV mass, volumes, stroke volume, and ejection fraction.
Does this herald the future substitution of 2D by 3D echo-
cardiography as the main tool to assess cardiac function in
clinical investigation and clinical practice? In this regard, the
main limitations of 2D echocardiography and planar ultra-
sound imaging in general relate to operator dependence and
impaired reproducibility because of the difficult registration
of 2D planes in 3D space. Although current 3D echocardiog-
raphy techniques still have limited versatility, the demonstra-
tion of a detailed mechanical analysis in a large population
study does announce the possibility that faster and more pow-
erful computing technology could, in a not so distant future,
bring 3D echocardiography to the forefront of quantitative
imaging not only in clinical investigation but also in clinical
practice. In this direction, the work by Hung et al8 represent
an important milestone.
In summary, cardiac remodeling, as demonstrated by
Hung et al,8 is characterized by concentric remodeling,
reduced stroke volume, and maintained ejection fraction.
Mechanically, although longitudinal shortening declines
with aging, ventricular torque increases, particularly among
women, to apparently compensate for reduced shortening and
maintain the ejection fraction. These changes are likely sec-
ondary to lifetime exposures to established as well as less well
characterized cardiovascular or novel risk factors, but could
also result from predetermined biological mechanisms that
intrinsically limit longevity in humans.1–4
Disclosures
None.
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KEY WORDS: Editorials ◼ aging ◼ cardiovascular system ◼ fibrosis ◼ imaging
◼ left ventricular ejection fraction
 The Aging Human Heart
João A.C. Lima

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