Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.
com
Review
►► Additional material is
published online only. To view
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​
heartjnl-2​ 017-​312114).
1
Heart Failure Research Group,
Baker Heart and Diabetes
Institute, Melbourne, Victoria,
Australia
2
Department of Cardiovascular
Medicine, Alfred Hospital,
Melbourne, Victoria, Australia
3
Faculty of Medicine, Nursing
and Health Sciences, Monash
University, Melbourne, Victoria,
Australia
4
Baker Heart and Diabetes
Institute, Melbourne, Victoria,
Australia
Correspondence to
Professor David M Kaye, Heart
Failure Research Group, Baker
Heart and Diabetes Institute,
Commercial Road, Melbourne
3004, Victoria, Australia; ​david.​
kaye@​baker.​edu.a​ u
Received 8 July 2017
Revised 27 September 2017
Accepted 28 September 2017
Published Online First
1 November 2017
To cite: Nanayakkara S,
Marwick TH, Kaye DM. Heart
2018;104:370–376.
370   Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
The ageing heart: the systemic and
coronary circulation
Shane Nanayakkara,1,2,3 Thomas H Marwick,2,4 David M Kaye1,2,3
Abstract
Most cardiovascular disease (CVD) occurs in patients
over the age of 60. However, most evidence-based
current cardiovascular guidelines lack evidence in an
older population, due to the under-representation of
older patients in randomised trials. Blood pressure
rises with age due to increasing arterial stiffness, and
stricter control results in improved outcomes. Myocardial
ischaemia is also more common with increasing age,
due to a combination of coronary artery disease and
myocardial changes. However, despite higher rates of
adverse outcomes, older patients are offered guideline-
based therapy less frequently. Frailty is an independent
predictor of mortality in adults over the age of 60, yet
remains poorly assessed; slow gait speed is a key marker
for the development of frailty and for adverse outcomes
following intervention. Few trials have assessed frailty
independent of age; however, there is evidence that
non-frail older patients derive significant benefit from
therapy, highlighting the urgent need to include frailty as
a measure in clinical trials of treatment in CVD.
In this review, the authors appraise the literature in
regard to the cardiovascular changes with ageing,
specifically in relation to the systemic and coronary
circulation and with a particular emphasis on frailty and
its implication in the evaluation and treatment of CVD.
Introduction
Advancing age is widely recognised as one of the
most significant risk factors for cardiovascular
disease (CVD), representing the complex biological
effects of the ageing process (table 1) together with
increased integrated exposure to environmental
risk factors. Consequently, over 50% of all CVD
occurs in those over the age of 60,1 and the preva-
lence of CVD in those over the age of 80 is 85%. As
a corollary, given the ageing nature of many popu-
lations, with particularly rapid growth of people
over the age of 85, an emerging epidemic of CVD
in the context of ageing has been widely predicted.
The proportion of patients over the age of 60 years
is expected to double from 11% to 22% by 2050,
with older adults (>60 years of age) outnumbering
the young (<5 years) in many countries within a
few years.2
Despite the importance of the ageing population
in the context of the CVD burden, the majority
of current cardiovascular (CV) guidelines do not
adequately reflect the older CVD population.3 This
represents the fact that the majority of randomised
studies have enrolled relatively homogeneous
cohorts of younger patients with fewer comorbid
conditions. By contrast, older patients are more
likely to suffer from comorbidities4 which may
modify the biology of specific forms of CVD, thereby
potentially introducing other unrelated endpoints.
Accordingly, there is a substantial under-representa-
tion of elderly patients in large-scale clinical CVD
trials and consequently the applicability of current
major CV trials and guidelines to older adults is
uncertain.
The archetypal patient with CVD is gradually
transforming from that represented in trials and
guidelines to an older, more complex individual
in whom treatment increasingly requires consider-
ation in regard to the pathophysiology of ageing and
its expression with CVD states, together with the
concomitant management of frailty and comorbid
disease. In these reviews, we focus specifically on
the impact of ageing on the evaluation and manage-
ment of cardiac disease.
Frailty
Frailty is recognised to be a strong determinant of
prognosis across the spectrum of CVD, and the
prevalence rapidly rises with age (figure 1). Among
the many relevant comorbidities associated with
ageing, frailty represents a state of increasing phys-
iological vulnerability which further modifies the
interaction between risk factors, disease progres-
sion and the phenotypic expression of CVD.5 This
key definition of vulnerability is variably assessed,
with no standardised scoring system proposed
by the major guideline groups. Multiple frailty
indices exist, variably accounting for coexisting
conditions, musculoskeletal capacity and cognitive
ability. The Fried Index, consisting of three ques-
tions and two physical measures, is well validated
for the measurement of frailty in older persons, as
is the Canadian Study of Health and Ageing Score.
Frailty may be secondary to the presence of cardiac
and non-cardiac diseases; in particular, low energy
expenditure, exhaustion and most notably slow gait
speed are significantly associated with the develop-
ment of frailty.6 Frailty also has a significant impact
on response to therapy; up to two-thirds (66%) of
patients undergoing percutaneous coronary inter-
vention (PCI) are frail, independently predictive
for mortality.7 Similar findings are seen in heart
failure (HF), cardiac surgery and transcutaneous
aortic valve implantation.
Extracardiac changes with ageing also play
a significant role in the progression to frailty
and limit the ability to adequately treat CVD
(figure 2). Glomerular filtration rate declines by
approximately 8 mL/min/1.73 m2 every decade,
beginning after the fourth decade, and limits the
use of certain pharmacological therapy and contrast
requiring interventions such as coronary angi-
ography. Frailty is also associated with cognitive
decline, particularly vascular dementia, leading to
difficulties with medication management, clouding
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com

Review

Table 1  Cardiac changes with ageing

Peripheral vasculature
Increased arterial stiffness
Progressive aortic dilatation
Increased wave reflection
Increased vasoconstriction and
impaired vasodilatation
Coronary arteries
Increased atherosclerosis
Increased prevalence of
subclinical plaque rupture
Increased coronary calcification
Reduced vasodilatory capacity
Reduced ability to form
collateral circulation
Impaired microvascular function
Atria
Increased left atrial fibrosis
Increased left atrial volume
Ventricle
Increased left ventricular mass
Reduced left ventricular cavity size
Increased left ventricular stiffness
Impaired passive filling
Increased left ventricular fibrosis
Conducting system
Increased prevalence of atrial
fibrillation
Progressive degenerative
fibrosis leading to bradycardia

the line between mental and physical disability, and compli-
cating the decision to consider invasive therapy. Finally, sarco-
penia is intrinsically linked to frailty, either as a consequence
of existing conditions or as a primary phenomenon related
to sedentary activity and poor nutrition, in combination with
age-related reductions in muscle repair. Although exercise
training may reduce the progression of muscle loss and improve
skeletal calcium handling, it remains unclear as to whether this
improves long-term CV outcomes. This combination of central
and peripheral changes culminates in a reduction in functional
capacity and peak VO2 (figure 3).
Although not all frailty is reversible, early identification of
the so-called ‘pre-frail’ state may permit targeted intervention
to prevent disability, and guide the appropriate use of therapy.
Current guidelines emphasise the importance of assessing frailty
and multimorbidity when making clinical decisions in elderly
patients (a summary of the recommendations from the most
recent guidelines with respect to elderly patients is presented in
online supplementary table 1). Clinical studies enrolling adults
should measure validated indices of frailty and compare the
effectiveness of interventions based on these markers rather than
age alone, as older non-frail adults may derive similar benefits
to younger patients; conversely, frail younger adults may have
higher rates of adverse consequences.
Systemic circulation and hypertension
The Systolic Blood Pressure Intervention Trial (SPRINT) showed
that intensive lowering of systolic blood pressure (SBP) targets is
associated with improved CV outcomes compared with standard
control in the elderly population.8 Although controversy exists
in regard to appropriate targets, with current guidelines relaxing
the target to less than 150 mm Hg in patients aged over 80
(although based on low-quality evidence9), a target SBP of less
than 140 mm Hg10 may be reasonable in the setting of appro-
priate risk stratification in regard to comorbidities and careful
monitoring during uptitration of therapy for orthostatic changes
and renal impairment. The benefit of more aggressive therapy
must be balanced however against issues of polypharmacy, risk
of orthostatic hypotension and worse renal function in older
patients; rather than considering age, frailty must be a primary
consideration in the choice of antihypertensive regimen. Further
studies are required to enhance the understanding of subgroups
at particular risk of adverse consequences of intensive blood
pressure (BP) control.
Pathophysiological changes in the systemic vasculature
Substantial changes in vascular structure occur with ageing,
most notably arterial stiffening and endothelial dysfunction,
as a consequence of an increase in collagen content and degra-
dation of elastin driven by upregulation of matrix metallopro-
teinases (particularly MMP-2), with further changes in vascular
smooth muscle cells, endothelial cells and inflammatory cells.11
Reduced nitric oxide bioavailability impairs vasorelaxation,
while increases in endothelin-1 promote vasoconstriction.12
Telomeres, genetic sequences designed to preserve chromosome
stability, progressively shorten with age, and reduced leucocyte
telomere length has been consistently associated with CVD,
particularly aortic stenosis and coronary artery disease (CAD).12
Telomeric ‘exhaustion’ promotes cellular senescence, a state in
which cell function is progressively lost while maintaining a
stable position within the cell cycle. Neurohormonal dysfunc-
tion and genetic factors12 have also been implicated in the devel-
opment and progression of ageing-related arterial stiffening and
hypertension.

Figure 1  Changes in blood pressure and vascular tone with age.

Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114 371
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com
Review
Figure 2  Extracardiac changes with ageing. FEV1, forced expiratory
volume in one second;  FVC, forced vital capacity; GFR, glomerular
filtration rate; LV, left ventricular; LA, left atrial.
Clinical consequences of vascular ageing
Hypertension in advancing age is principally characterised by
elevated SBP. SBP increases progressively with age, while diastolic
Figure 3  Physiological basis of reduction in peak VO2 with age.
372
blood pressure (DBP) rises until around age 50, in concert with
peripheral vascular resistance (Figure 4). DBP subsequently falls,
due to the ageing-related increase in arterial stiffness, thereby
leading to an increase in pulse pressure. Both SBP and DBP are
associated with CV mortality in older adults. Assessment of arte-
rial BP is further compounded by the presence of pulse wave
reflection and amplification, which is dependent on variables
including patient body habitus, age and heart rate. Although
pulse wave amplification occurs to a greater extent in younger
individuals, central aortic pulse pressure increases significantly
more than brachial pulse pressure in older adults, and is a better
predictor of CV outcome than peripheral measures.13
Investigations
Given the physiological implications of arterial stiffening and
its confounding effects on central BP measurement via wave
reflection, a variety of tools have been developed to non-inva-
sively assess the central circulation. In particular, methods based
on the principle of applanation tonometry have been applied
to measure pulse wave velocity (PWV; the velocity at which an
arterial wave travels through the systemic circulation, a measure
of arterial stiffening) and to derive haemodynamic parameters
including central aortic BP, augmentation pressure (difference
between the first and second systolic peaks) and the augmenta-
tion index (the augmentation pressure expressed as a percentage
of the pulse pressure). Age is an important determinant of PWV.
Aortic PWV demonstrates a non-linear correlation with age with
Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com
Figure 4  Rise in frailty with increasing age. PWV, pulse wave velocity.
a pronounced rise after age 50, while brachial PWV remains
linear (figure 4).14 The rise in central aortic pressure induces
structural changes; the aorta undergoes significant dilatation,
doubling in intimal surface area between the second and the
sixth decade of life.15 These well-recognised changes lead to a
further increase in arterial stiffness and subsequent decrease in
the aortic reservoir function.
PWV is predictive of the development of hypertension, and
an independent predictor of CVD and mortality. In a study of
141 adults over the age of 70 hospitalised for both CV and
non-CV reasons, a PWV>17.7 m/s was found to be a strong
predictor of CV mortality (OR 4.6, 95% CI 1.4 to 15.7),16 inde-
pendent of BP and antihypertensive therapy. In contrast, changes
in augmentation index are more prominent in subjects under
the age of 50. As such, the augmentation index may be a more
reliable marker of arterial ageing in younger individuals, while
aortic PWV is more appropriate in older adults.
The value of ambulatory BP monitoring has been well estab-
lished in diagnosis, assessment of drug efficacy and to assess
nocturnal dipping status. In a study of older adults with isolated
systolic hypertension, ambulatory SBP alone predicted CV risk
more accurately than conventional clinic-based BP.17 Ambulatory
BP monitoring is an independent predictor of CV mortality (HR
1.51 for every 10 mm Hg rise in SBP)—in patients without CVD,
office BPs did not predict adverse CV outcomes,18 and of note
the diastolic ambulatory BP carried greater prognostic signifi-
cance in multivariate analysis. Importantly, in these patients
the U-shaped relationship often seen with respect to mortality
was not noted, perhaps due to the absence of coronary disease.
Nocturnal SBP is also a strong predictor of CV death, with a
relative risk increase of 18% for each 10 mm Hg in night-time
SBP.19 Furthermore, the ambulatory white coat effect is higher
in older adults, and the divergence between ambulatory BP and
clinic BP also widens in the very elderly.20
Treatment
Early trials of antihypertensive therapy excluded older adults,
despite the prevalence of hypertension in the elderly. In the
late 1980s, the Systolic Hypertension in the Elderly Program
(SHEP)21 and the Systolic Hypertension in Europe22 trials using
chlorthalidone/atenolol or nitrendipine/enalapril/hydrochloro-
thiazide respectively demonstrated significant benefit in patients
aged >70 years. The Hypertension in the Very Elderly Trial
(HYVET)23 randomised subjects >80 years (mean age 84 years)
to indapamide or placebo, with perindopril added if the target
BP was not reached. Active treatment was associated with a
Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
Review
21% reduction in all-cause mortality. SPRINT-Senior then eval-
uated the impact of an intensive BP target (<120 mm Hg) in
2636 patients ≥75 years of age, demonstrating lower all-cause
mortality and CV events, at the expense of numerically higher
values for hypotension (HR 1.71, 95% CI 0.97 to 3.09), syncope
(HR 1.23, 95% CI 0.76 to 2.00) and renal impairment (HR
1.41, 95% CI 0.98 to 2.04).
A recent systematic review and meta-analysis of over 10 000
patients by Bavishi et al24 confirmed the benefit of lower BP
targets (<140 mm Hg) in older adults. Over a mean follow-up
of 3.1 years, patients randomised to intensive control had a 33%
reduction in CV mortality with a significant decrease (37%)
in the risk for HF; however, there was a small increase in the
risk of renal failure, driven predominantly by the patients in
the SPRINT trial without chronic kidney disease at baseline.
Hypotension and syncope may be more common, highlighting
the importance of incremental dose adjustments and judicious
monitoring following medication changes.
Frailty is an important differentiator of overall health in the
elderly; however, few trials have specifically assessed the bene-
fits of antihypertensive therapy in regard to functional status.
Secondary analysis of the SHEP data demonstrated benefit only
in patients without a limitation to physical ability25; however, a
subanalysis of the HYVET group revealed no interaction between
effect of treatment for hypertension and frailty.26 Further studies
are required to investigate this association, particularly in regard
to the impact of frailty on the ideal BP target and subsequent
impact on management.
All elderly patients should be treated to a target BP of less
than 150/80, as per current guidelines. The decision to offer
more aggressive BP reduction, with targets below 140 mm Hg
systolic, must consider that the significant reduction in mortality
(1.5%) comes at the cost of a 0.5% increase in renal impair-
ment. A careful assessment of frailty, autonomic function, coro-
nary disease and myocardial function must be considered prior
to choosing the appropriate BP target. Critically, the majority
of trials are based on seated BP following 5 min of rest, which
should be replicated in the clinic environment when applying
these findings to individual patients.
Coronary circulation
Epidemiology
Increasing population age, independent of traditional risk
factors, is projected to result in a significant increase in the inci-
dence and prevalence of CAD.27 Of all CVDs, CAD is the most
373
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com
Review
common cause of mortality and morbidity in the elderly. Older
adults are more likely to suffer an acute coronary syndrome,
and to develop subsequent adverse events including HF, renal
failure and bleeding. Unfortunately, the majority of data avail-
able exclude patients over the age of 75, and the trials that do
include older adults suffer from significant selection bias as frail
patients are often excluded, highlighting the need for prospec-
tive randomised trials in a wide range of older patients.
Pathophysiology
Despite the prominent role of ageing as a risk factor of CAD,
the specific mechanisms remain poorly understood. Both vessel
ageing and atherosclerosis share many similar pathogenic path-
ways. Subclinical plaque rupture is frequent in patients with
atherosclerosis, and relies on adequate vascular smooth muscle
cell proliferation and function, both impaired with cellular senes-
cence.28 Endothelial cells become dysmorphic with increasing
age, with a reduction in their functional activity.28 Vascular
smooth muscle cells become proinflammatory, with upregu-
lation of chemokines, adhesion molecules and increased levels
of interleukin 6, and alterations in hormonal factors adversely
affect coronary artery smooth muscle cell proliferation, apop-
tosis and function.29
Beyond epicardial coronary disease as a trigger for myocar-
dial ischaemia, the combination of age-associated left ventricular
hypertrophy increases oxygen demand, while supply is limited
by coronary microvascular dysfunction, prolonged systolic ejec-
tion duration and reduced coronary perfusion pressure facil-
itating the development of myocardial ischaemia. While the
density of coronary vessels is maintained in otherwise healthy
older adults, left ventricular perfusion is reduced at the arteri-
olar level due to thickening of the tunica media.12 Increasing age
also limits the ability of the coronary vascular bed to augment
blood flow through vasodilation and neovascularisation, in part
due to increased endothelin-1 activity and reduced nitric oxide
availability and responsiveness30 and a reduced capacity to form
collaterals.31
Clinical presentation
CAD in the elderly is more frequent, and displays unique charac-
teristics compared with younger patients. Older adults are more
likely to have left main stenosis, multivessel disease and impaired
left ventricular systolic function. Patients over 75 are also less
likely to present with typical symptoms of angina; atypical symp-
toms such as dyspnoea and nausea are much more common.32
Patients over the age of 65 are more likely to present to hospital
later; up to 25% present after 6 hours following symptom onset,
particularly in diabetics and those with a history of angina.33
Older adults are also more likely to have their initial diagnosis
labelled non-ischaemic due to the heterogeneity and atyp-
ical nature of their presentation. ECGs may be less diagnostic
than younger patients due to higher rates of conducting system
disease, in particular left bundle branch block. As a consequence,
diagnosis may be delayed until confirmatory biomarkers can be
obtained.
Investigations
Stress testing
Stress testing, either using ECG or imaging, is more difficult in
elderly patients. Functional capacity can be accurately assessed
using exercise, however may be limited to non-cardiac contrib-
utors such as deconditioning, osteoarthritis, muscle weakness,
neurological and pulmonary disease. Inability to perform
374
adequate exercise increases the reliance on pharmacological
testing, thereby removing the prognostic information afforded
by evaluating exercise workload and haemodynamic response.
Given the common occurrence of baseline ECG abnormali-
ties or known CAD, stress imaging is also recommended over
stress ECG testing.34 While pharmacological stress echocar-
diography is commonly used in the elderly, it is important
to note that the effect of dobutamine varies with age, with
blunted inotropic response in the older population, and dobu-
tamine-related hypotension and ventricular arrhythmias are
more common in the elderly population, limiting widespread
use. Limitations in assessing wall motion abnormalities, due to
poor imaging in the context of small rib spaces or concomitant
lung disease, may be overcome with the use of echocardio-
graphic contrast agents.
CT coronary angiography
Coronary artery calcification is an important predictor of CV
events and long-term survival. CT provides a non-invasive
assessment of coronary anatomy and provides excellent negative
predictive values in patients at low risk of coronary disease. CT
coronary angiography has been considered less useful in elderly
populations due to higher rates of pre-existing coronary disease
and the gradual rise in coronary calcification with age. Coronary
calcification generates artefact reducing specificity and diag-
nostic accuracy, and is not recommended in patients with signifi-
cant calcification. Importantly, elderly patients without coronary
calcium have a 5-year survival of over 98%, similar to that seen
in other age groups.35 In a large cohort of patients undergoing
calcium scoring and longitudinal follow-up, absolute calcium
scoring was more accurate in prediction of cardiac events than
age-gender-ethnicity percentiles, with cut points of 100 and
400 performing best36; phenotypic characterisation based on
anatomical and physiological variables may be more prognostic
than based on demographic variables such as age alone.
Fractional flow reserve
Two primary contributors to coronary flow are epicardial
stenosis and microvascular resistance. Angiographic appear-
ance alone is not a reliable marker of ischaemia, particularly
in stenoses between 50% and 70% of the luminal diameter.
Fractional flow reserve (FFR) is now commonly used to deter-
mine the haemodynamic significance of epicardial stenoses at
the time of coronary angiography. FFR-guided PCI is beneficial
regardless of age; however, older patients have fewer function-
ally significant lesions despite a similar angiographic appear-
ance.37 The higher values for FFR in older patients may be due
to age and comorbidity-related vascular changes, increasing
microvascular resistance thereby decreasing the translesional
pressure gradient; the clinical consequence of this finding is
not known. Jin et al38 assessed intermediate stenoses using FFR
and intravascular ultrasound in older patients (mean age 71),
demonstrating that age independently predicted FFR and func-
tional significance (defined as FFR≤0.8) as well as traditional
predictors such as minimal luminal area, stenosis diameter,
lesion length and diameter. Older patients were more likely
to show evidence of microvascular dysfunction, smaller vessel
size and more diffuse disease. Data regarding the impact of age
on iFR (instantaneous wave-free ratio) are not yet available; of
note, the discordance between FFR and iFR values is larger in
patients with a greater ability to reduce microvascular resistance
with hyperaemia.39
Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com
Treatment
Coronary angiography and PCI
Compared with community cohorts, patients enrolled in clin-
ical trials are younger with fewer comorbidities. Analysis from
the CRUSADE Quality Improvement Initiative demonstrated
trial patients were younger (median 65 vs 68 years), with
less renal impairment (8.5% vs 13.5%) and less HF (13.2 vs
19%).40 Patients in the elderly and very elderly groups are most
under-represented, constituting just 2% of trial populations
in major studies of patients with non-ST elevation acute coro-
nary syndromes (NSTEACS). Similar findings are seen in other
cohorts, with more comorbid conditions and higher rates of
multivessel CAD. Guideline-recommended therapy is underused
in elderly patients. Large retrospective data analyses demon-
strate that older patients are more likely to suffer from previous
cardiac disease and comorbidity, less likely to receive specialist
care and presented increasing contraindications to medication
use, with less than a third of patients with NSTEACS receiving
clopidogrel.41 Fewer than half of patients over the age of 75
underwent early invasive treatment despite a higher likelihood
of positive biomarkers and baseline risk; patients receiving
guideline-based therapy had a significantly lower likelihood of
in-hospital mortality.
Transradial PCI has consistently demonstrated reductions in
CV mortality. Despite increased technical difficulty in elderly
patients owing to greater radial and brachiocephalic tortuosity,
conversion is uncommon and the significant reduction in major
bleeding has elevated radial access to a class I recommendation
in most recent European Society of Cardiology (ESC) guidelines
for ST elevation myocardial infarction (STEMI).42
Stable angina
Several studies have demonstrated equivalent benefits of PCI in
younger and older cohorts of patients; however, older adults
have higher rates of procedural complications and adverse effects
from medication. The TIME study43 compared optimal medical
therapy to PCI in patients aged >75 years with stable angina.
Although both groups demonstrated improvements in quality
of life and symptomatology, the benefit was significantly greater
in those undergoing PCI. A long-term analysis of patients over
the age of 65 confirmed early and late survival benefits in those
receiving guideline-recommended therapy.44 Earlier therapy was
associated with significant gains in life expectancy, due to pres-
ervation of myocardium through reduction of infarct size and
prevention of reinfarction.
Acute coronary syndromes
Two studies have specifically sought to answer the question of
utilising an invasive strategy in older adults. The After Eighty
study randomised patients with unstable angina/non-ST eleva-
tion myocardial infarction (UA/NSTEMI) over the age of 80 to
either an invasive strategy or optimal medical therapy alone.45
Myocardial infarction and need for urgent revascularisation
were significantly lower in the invasive group, although there
was no significant difference in all-cause mortality. Similarly, the
Italian Elderly ACS study46 randomised patients ≥75 years with
UA/NSTEMI to either an early invasive strategy or conservative
arm (with coronary angiography for recurrent ischaemia); a
significant reduction in the composite endpoint (death, myocar-
dial infarction, disabling stroke, CV hospitalisation and major
bleeding) was seen in patients with an initial troponin elevation
(HR 0.43, 95% CI 0.23 to 0.8) but not in those with a normal
initial troponin.
Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
Review
Converse to the ambiguous results seen in UA/NSTEMI,
patients with STEMI derive significant benefit from reperfu-
sion regardless of age. Bueno et al47 pooled the results of three
studies comparing PCI and fibrinolysis in older patients, with
PCI strongly favoured (HR 0.63) and recommended for older
adults in the most recent ESC guidelines.42
Coronary artery bypass grafting
The risks of coronary artery bypass grafting (CABG) in elderly
patients have gradually reduced over the past few decades;
however, the perception of poor postoperative outcomes based
on chronological age alone persists. Peril-operative risk is higher,
due to the greater presence of comorbid conditions and worse
functional status. Although early mortality is greater, mid-term
mortality is similar.48 Recent data have shown that elderly
patients can also derive significant quality of life benefits from
cardiac surgery.49 Nevertheless, concomitant frailty can signifi-
cantly influence the benefit derived from CABG; however, this
can be difficult to assess. Recent small studies using basic frailty
measures have been applied in both PCI and cardiac surgery
patients, highlighting the disease-modifying effect of frailty.50
In summary, elderly patients are more difficult to diagnose on
both clinical and imaging grounds, and a higher index of suspi-
cion must be held for the presence of coronary disease. Despite
the fear of increase in complications following intervention,
elderly patients derive significant benefit from guideline-based
therapy, particularly those with troponin positive acute coronary
syndromes. The choice of intervention must be based more on
an appreciation of comorbidity and frailty, with specific regard
to the impact of renal impairment, rather than chronological age
alone.
Conclusion
Despite substantial advances in the management of patients
with CVD, the applicability of the current body of knowledge
to the ageing population remains uncertain. It is imperative
that a greater emphasis be placed upon the inclusion of older
patients with manifest CVD in clinical trials, with a focus on
understanding the frail subgroup. In conjunction, improve-
ments in the management of CV conditions in the elderly will
increasingly be dependent on a comprehensive assessment of the
individual patient’s health in the context of frailty, multimorbid
status and functional capacity. Finally, and perhaps most impor-
tantly, a reappraisal of the relative importance of clinical trial
endpoint measures, such as survival in comparison to quality of
life, obtained by quantitative patient-centred evaluation tools
should be conducted in older individuals with CVD.
Contributors  The paper was conceived by SN and DMK. The first draft was
prepared by SN, with critical revision by both THM and DMK. All authors reviewed
and significantly contributed to the content of the paper.
Funding  SN is supported by a Health Professional Scholarship from the Heart
Foundation of Australia (101116). DMK is supported by the National Health and
Medical Research Council of Australia.
Competing interests  None declared.
Provenance and peer review  Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
References
1 As G, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics-2013 update:
a report from the American Heart Association. Circulation 2013;127.
375
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com
Review
2 Fuster V. Changing demographics: a new approach to global health care due to the
aging population. J Am Coll Cardiol 2017;69:3002–5.
3 Rich MW, Chyun DA, Skolnick AH, et al. Knowledge gaps in cardiovascular care of the
older adult population. Circulation 2016:CIR.0000000000000380.
4 Ahluwalia SC, Gross CP, Chaudhry SI, et al. Change in comorbidity prevalence
with advancing age among persons with heart failure. J Gen Intern Med
2011;26:1145–51.
5 Rowe R, Iqbal J, Murali-Krishnan R, et al. Role of frailty assessment in patients
undergoing cardiac interventions. Open Heart 2014;1:e000033.
6 Sergi G, Veronese N, Fontana L, et al. Pre-frailty and risk of cardiovascular disease in
elderly men and women: the Pro.V.A. study. J Am Coll Cardiol 2015;65:976–83.
7 Singh M, Rihal CS, Lennon RJ, et al. Influence of frailty and health status on outcomes
in patients with coronary disease undergoing percutaneous revascularization. Circ
Cardiovasc Qual Outcomes 2011;4:496–502.
8 Williamson JD, Supiano MA, Applegate WB, et al. SPRINT Research Group. Intensive
vs Standard blood pressure control and cardiovascular disease outcomes in adults
aged ≥75 Years: a randomized clinical trial. JAMA 2016;315:2673–82.
9 James PA, Oparil S, Carter BL, et al. Evidence-based guideline for the management of
high blood pressure in adults. JAMA 2014;2014:507.
10 Chobanian AV. Hypertension in 2017-What Is the right target? JAMA 2017;317:579.
11 Chung HY, Sung B, Jung KJ, et al. The molecular inflammatory process in aging.
Antioxid Redox Signal 2006;8:572–81.
12 Paneni F, Canestro CD, Libby P, et al. The Aging cardiovascular system: understanding
it at the cellular and clinical level. 2016.
13 Roman MJ, Devereux RB, Kizer JR, et al. Central pressure more strongly relates to
vascular disease and outcome than does brachial pressure: the Strong Heart Study.
Hypertension 2007;50:197–203.
14 McEniery CM, Yasmin, Hall IR, et al. Normal vascular aging: differential effects on
wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial
(ACCT). J Am Coll Cardiol 2005;46:1753–60.
15 Virmani R, Avolio AP, Mergner WJ, et al. Effect of aging on aortic morphology in
populations with high and low prevalence of hypertension and atherosclerosis.
Comparison between occidental and Chinese communities. Am J Pathol
1991;139:1119–29.
16 Meaume S, Benetos A, Henry OF, et al. Aortic pulse wave velocity predicts
cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol
2001;21:2046–50.
17 Staessen JA, et al. Predicting cardiovascular risk using conventional vs ambulatory
blood pressure in older patients with systolic hypertension. JAMA 1999;282:539.
18 Hansen TW, Jeppesen J, Rasmussen S, et al. Ambulatory blood pressure and mortality:
a population-based study. Hypertension 2005;45:499–504.
19 Burr ML, Dolan E, O’Brien EW, et al. The value of ambulatory blood pressure in older
adults: the dublin outcome study. Age Ageing 2008;37:201–6.
20 Bulpitt CJ, Beckett N, Peters R, et al. Does white coat hypertension require treatment
over age 80?: Results of the hypertension in the very elderly trial ambulatory blood
pressure side project. Hypertension 2013;61:89–94.
21 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug
treatment in older persons with isolated systolic hypertension. Final results of the
Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–64 http://
www.​ncbi.​nlm.​nih.​gov/p​ ubmed/​2046107.
22 Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo
and active treatment for older patients with isolated systolic hypertension. The Systolic
Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–64.
23 Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years
of age or older. N Engl J Med 2008;358:1887–98.
24 Bavishi C, Bangalore S, Messerli FH. Outcomes of intensive blood pressure lowering in
older hypertensive patients. J Am Coll Cardiol 2017;69:486–93.
25 Charlesworth CJ, Peralta CA, Odden MC. Functional status and antihypertensive
therapy in older adults: a new perspective on old data. Am J Hypertens
2016;29:690–5.
26 Warwick J, Falaschetti E, Rockwood K, et al. No evidence that frailty modifies
the positive impact of antihypertensive treatment in very elderly people: an
investigation of the impact of frailty upon treatment effect in the Hypertension
in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study
of antihypertensives in people with hypertension aged 80 and over. BMC Med
2015;13:78.
376
27 Odden MC, Coxson PG, Moran A, et al. The impact of the aging population on
coronary heart disease in the United States. Am J Med 2011;124:827–33.
28 Wang JC, Aging BM. Aging and atherosclerosis. Circ Res 2012;111:245–59.
29 Wei K, Díaz-Trelles R, Liu Q, et al. Developmental origin of age-related coronary artery
disease. Cardiovasc Res 2015;107:287–94.
30 Nguyen PK, Terashima M, Fair JM, et al. Physical activity in older subjects is associated
with increased coronary vasodilation: the ADVANCE study. JACC Cardiovasc Imaging
2011;4:622–9.
31 Epstein SE, Lassance-Soares RM, Faber JE, et al. Effects of aging on the collateral
circulation, and therapeutic implications. Circulation 2012;125:3211–9.
32 Milner KA, Vaccarino V, Arnold AL, et al. Gender and age differences in chief
complaints of acute myocardial infarction (Worcester Heart Attack Study). Am J
Cardiol 2004;93:606–8.
33 Sheifer SE, Rathore SS, Gersh BJ, et al. Time to presentation with acute myocardial
infarction in the elderly: associations with race, sex, and socioeconomic characteristics.
Circulation 2000;102:1651–6 http://www.​ncbi.​nlm.​nih.​gov/p​ ubmed/​11015343.
34 Montalescot G, Sechtem U, Achenbach S, et al. ESC guidelines on the management of
stable coronary artery disease. Eur Heart J 2013;2013:2949–3003.
35 Tota-Maharaj R, Blaha MJ, McEvoy JW, et al. Coronary artery calcium for the
prediction of mortality in young adults 75 years old. Eur Heart J 2012;33.
36 Budoff MJ, Nasir K, McClelland RL, et al. Coronary calcium predicts events better with
absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic
Study of Atherosclerosis). J Am Coll Cardiol 2009;53:345–52.
37 Lim HS, Tonino PA, De Bruyne B, et al. The impact of age on fractional flow reserve-
guided percutaneous coronary intervention: a FAME (Fractional Flow Reserve versus
Angiography for Multivessel Evaluation) trial substudy. Int J Cardiol 2014;177:66–70.
38 Jin X, Lim HS, Tahk SJ, et al. Impact of age on the functional significance of
intermediate epicardial artery disease. Circ J 2016;80:1583–9.
39 Lee JM, Hwang D, Park J, et al. Physiologic mechanism of discordance between
instantaneous wave-free ratio and fractional flow reserve: Insight from (13)
N-ammonium positron emission tomography. Int J Cardiol 2017;243:91–4.
40 Kandzari DE, Roe MT, Chen AY, et al. Influence of clinical trial enrollment on the
quality of care and outcomes for patients with non-ST-segment elevation acute
coronary syndromes. Am Heart J 2005;149:474–81.
41 Alexander KP, Roe MT, Chen AY, et al. Evolution in cardiovascular care for elderly
patients with non-ST-segment elevation acute coronary syndromes: results
from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol
2005;46:1479–87.
42 Ibanez B, James S, Agewall S, et al. ESC Guidelines for the management of acute
myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J
2017;2017:2569–619.
43 , Aldermann ETIME Investigators ECSS; TIME Investigators. Trial of invasive versus
medical therapy in elderly patients with chronic symptomatic coronary-artery disease
(TIME): a randomised trial. Lancet 2001;358:951–7.
44 Bucholz EM, Butala NM, Normand ST, et al. Association of guideline-based
admission treatments and life expectancy after myocardial infarction in elderly
medicare beneficiaries. J Am Coll Cardiol 2016;67:2378–91.
45 Tegn N, Abdelnoor M, Aaberge L, et al. Invasive versus conservative strategy in
patients aged 80 years or older with non-ST-elevation myocardial infarction or
unstable angina pectoris (After Eighty study): an open-label randomised controlled
trial. Lancet 2016;387:1057–65.
46 Savonitto S, Cavallini C, Petronio AS, et al. Early aggressive versus initially conservative
treatment in elderly patients with non-ST-segment elevation acute coronary syndrome:
a randomized controlled trial. JACC Cardiovasc Interv 2012;5:906–16.
47 Bueno H, Betriu A, Heras M, et al. Primary angioplasty vs. fibrinolysis in very old
patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto Agudo de
miocardio eN Ancianos) randomized trial and pooled analysis with previous studies.
Eur Heart J 2011;32:51–60.
48 Ascione R, Rees K, Santo K, et al.  Coronary artery bypass grafting in patientsover 70
years old: The influence of age and surgical technique onearly and mid-term clinical
outcomes. EuropeanJournal of Cardio-thoracic Surgery. Oxford: Oxford University
Press, 2002:124–8.
49 Shan L, Saxena A, McMahon R, et al. Coronary Artery Bypass Graft Surgery in the
Elderly. Circulation 2013;128.
50 Afilalo J, Eisenberg MJ, Morin JF, et al. Gait speed as an incremental predictor of
mortality and major morbidity in elderly patients undergoing cardiac surgery. J Am
Coll Cardiol 2010;56:1668–76.
Nanayakkara S, et al. Heart 2018;104:370–376. doi:10.1136/heartjnl-2017-312114
 Downloaded from http://heart.bmj.com/ on March 9, 2018 - Published by group.bmj.com

The ageing heart: the systemic and coronary

circulation
Shane Nanayakkara, Thomas H Marwick and David M Kaye

Heart2018 104: 370-376 originally published online November 1, 2017

doi: 10.1136/heartjnl-2017-312114

Updated information and services can be found at:

http://heart.bmj.com/content/104/5/370

These include:

References This article cites 44 articles, 16 of which you can access for free at:
http://heart.bmj.com/content/104/5/370#ref-list-1

Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/