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Journal of the American College of Cardiology
© 2008 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Aging and Defective Healing,
Adverse Remodeling, and
Blunted Post-Conditioning in
the Reperfused Wounded Heart*
Bodh I. Jugdutt, MBCHB, MSC, DM, FRCPC,
FACC,†‡ Anwar Jelani, MD†
Edmonton, Canada
Optimal healing of the wounded heart is critical for the
preservation of structural and functional integrity of the
pumping chambers and for survival with a favorable outcome. This is especially important in elderly patients, in
whom myocardial infarction (MI) is prevalent and in whom
defective healing may promote adverse remodeling, thereby
jeopardizing outcome.
Healing post-MI. Acute MI triggers a host of biochemical, molecular, and cellular changes that lead to the highly
complex, dynamic, and concurrent processes of healing,
repair, and remodeling in an attempt to repair structural
damage and preserve left ventricular (LV) function (1).
See pages 1384 and 1393
Healing after MI involves an orchestrated sequence of:
1) acute and chronic inflammation; 2) tissue repair with
fibroblast proliferation, extracellular matrix and collagen
deposition, myofibroblast and scar formation; and 3) structural and functional remodeling of infarcted and noninfarcted myocardium through cardiomyocyte hypertrophy,
with little regeneration, and some angiogenesis (1). The
intensity and rate of the healing, reparative, adaptive/
maladaptive remodeling responses and functional outcome
depend to a large extent on infarct size (1,2). Indeed small
and predominantly subendocardial or non–ST-segmentelevation myocardial infarctions (NSTEMIs) usually heal
within 6 weeks in humans, with formation of a firm scar and
preservation of LV function, size, and shape (1). However,
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the †Division of Cardiology, Department of Medicine, and ‡Cardiovascular
Research Group, University of Alberta, Edmonton, Canada. This work was supported
in part by grants (Dr. Jugdutt) from the Heart and Stroke Foundation of Canada and
the Canadian Institutes of Health, Ottawa, Ontario, Canada.
Vol. 51, No. 14, 2008
ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2007.12.027
severe and extensive injury, as with large and predominantly
transmural or ST-segment-elevation myocardial infarctions
(STEMIs), result in delayed healing over nearly 6 months in
humans, and induce significant adverse regional and global
LV remodeling that impacts negatively on outcome and
survival (1). Optimizing healing after MI therefore deserves
high priority in cardiovascular research (1,2).
Aging and post-MI healing. Aging has become a major
health issue and socioeconomic burden worldwide. The
aging population is increasing, and with it, the morbidity
and mortality that are largely caused by impaired wound
healing and other defects. Based on growth in the U.S.
between 2003 and 2004, the Census Bureau predicted an
increase in the number of Americans age 65 years and over
between 2004 and 2050, from 12% (36.3 million) to 21%
(86.7 million). Despite improved therapies, nearly 85% of
all cardiovascular deaths over the last 2 decades occurred in
the 65-and-over age group (3). The average age for a first
MI is 66 years in men and 70 years in women (3). Several
studies have identified age as a strong predictor of adverse
events after acute coronary syndromes and elderly persons as
being a high-risk subgroup (4). Nearly 50% of hospital
admissions for acute MI and 80% who die are age 65 years
and over (2). The age-related increase in post-MI mortality
is not just due to larger infarcts. Post-MI heart failure is also
increasing, and adverse remodeling is more common in
patients age 65 years and over. Most post-STEMI deaths
are caused by LV free wall rupture, and fibrinolytic therapy
increases this risk in elderly patients (5). Therapeutic
strategies over the last decade have improved survival mainly
in patients who are younger than 65 years. Because aging is
an important determinant of post-MI healing (Fig. 1) and
affects most factors that influence healing (Fig. 2), more
detailed studies that target aging and elderly persons are
justified.
Aging is associated with impaired immunity and comorbidities that contribute to impaired healing after MI (Figs.
1 and 2). Aging also impairs the potential of stem cells and
progenitor cells for myocardial regeneration. Polypharmacy,
which is also common in elderly patients, raises concerns
regarding interactions and pleiotropic effects that impact
inflammation and infarct collagen during post-MI healing.
Several commonly used drugs impair healing (i.e., antiinflammatory agents for arthritis) and collagen synthesis
(i.e., angiotensin-converting enzyme inhibitors, angiotensin
II type 1 receptor blockers, aldosterone antagonists, endothelin antagonists, and statins) (1,2,6). These drugs may
prolong the time window of vulnerability for adverse LV
remodeling during post-MI healing (1), and the effect may
be more pronounced in elderly persons. Greater caution is
needed with these drugs during post-MI healing in elderly
persons. The issue of gender and drug effects, including
hormone therapy, during post-MI healing in elderly men
versus women also needs to be addressed.
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Figure 1
Jugdutt and Jelani
Editorial Comment
JACC Vol. 51, No. 14, 2008
April 8, 2008:1399–1403
Known and Potential Factors in Healing After Myocardial Infarction
ACE-I ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin II type 1 receptor blocker; MMP ⫽ matrix metalloproteinase; NAD(P) ⫽ nicotinamide adenine dinucleotide phosphate; NF-␬B ⫽ nuclear factor -␬B; NSAID ⫽ nonsteroidal antiinflammatory drug; OFR ⫽ oxygen free radical; RAAS ⫽ renin-angiotensin-aldosterone system;
SLPI ⫽ secretory leucocyte protease inhibitor; SPARC ⫽ secreted protein acidic and rich in cysteine; TIMP ⫽ tissue inhibitor of MMP; TGF ⫽ transforming growth factor.
Abrupt reperfusion and post-MI healing. Coronary
reperfusion in acute MI improves survival and is undisputedly the early therapy of choice. Evidence indicates that
early reperfusion during small and modest STEMI can limit
infarct size and adverse LV remodeling or even abort
STEMI altogether. However, late reperfusion is associated
with reperfusion injury, myocardial stunning and persistent
Figure 2
LV dysfunction, microvascular damage and no-reflow, excess free radicals, apoptosis and necrosis, enhanced degradation of the extracellular matrix, decreased collagen crosslinking and tensile strength of infarct scars, enhanced
inflammation, accelerated healing, and persistent LV remodeling (1,7–9). Reperfusion has been shown to decrease
infarct scar size within 6 months in humans with average
Aging-Related Defects That Influence Post-MI Healing
1 ⫽ increased, enhanced; 2 ⫽ decreased, impaired; Ang ⫽ angiotensin; CPC ⫽ cardiac progenitor cell; CSC ⫽ cardiac stem cell;
EPC ⫽ endothelial progenitor cell; MMP ⫽ matrix metalloproteinase; NO ⫽ nitric oxide; TGF ⫽ transforming growth factor; TLR ⫽ toll-like receptor.
Jugdutt and Jelani
Editorial Comment
JACC Vol. 51, No. 14, 2008
April 8, 2008:1399–1403
ages between 61 and 69 years (10,11). Elderly patients are at
greater risk after reperfused STEMI (5,9).
In this issue of the Journal, Bujak et al. (12) tested the
hypothesis that aging-related changes in inflammatory mediator expression and impaired responsiveness of senescent
cells to growth factors may be responsible for defective
infarct healing and adverse remodeling after reperfused MI.
They focused on cellular mechanisms and compared a
comprehensive array of histomorphometric, molecular, and
echocardiographic end points in young (2 months to 3
months) and senescent (⬎2 years) mice as well as the
response of isolated cardiac fibroblasts to transforming
growth factor-beta (TGF-␤) stimulation. They convincingly show 4 defects in older mice during post-MI healing:
1) impaired inflammation with decreased and delayed neutrophil and macrophage infiltration, reduced cytokine and
chemokine expression, and impaired phagocytosis of dead
cardiomyocytes; 2) impaired healing with decreased myofibroblast density and markedly decreased collagen deposition
in the infarct scar; 3) enhanced dilative and hypertrophic
remodeling and more systolic dysfunction; and 4) a blunted
fibroblast response to TGF-␤1. Temporally, despite similar
infarct size, reperfused MI in young mice induced intense
inflammation after 24 h and replacement with granulation
tissue within 72 h (consistent with enhanced inflammation
and accelerated healing after reperfusion), whereas healing
in the older mice was delayed beyond 7 days. Although the
study was not powered to address mortality, there was a
trend for more deaths in the old than young mice after
coronary occlusion and reperfusion. The overall findings
indicated that suppressed inflammation, delayed repair, and
reduced infarct collagen in senescent mice lead to adverse
LV remodeling, providing compelling arguments for modifying therapy in elderly persons.
Bujak et al. (12) were careful to use a closed-chest snare
model to avoid the effects of surgery on the inflammatory
variables. They wisely warn against extrapolation of findings
from young animals to elderly human patients and against
using anti-inflammatory therapies in reperfused MI. However, a third caveat concerns extrapolation of findings in
mice to humans based on at least 3 lines of evidence. First,
the inflammatory response differs between mice and dogs.
Dewald et al. (13) showed that infarcts in young mice (1.5
months to 2 months) show similar rapid inflammatory
infiltration, clearance of dead cardiomyocytes, and induction
of endothelial adhesion molecules, cytokines, and chemokines as dogs; however, unlike dogs, mice show only
transient macrophage infiltration and up-regulation of macrophage colony-stimulating factor (M-CSF), no significant
accumulation of mast cells, no induction of stem cell factor
(SCF) that is a growth factor for mast cells, and more
abundant angiogenesis. Second, the response to antiinflammatory agents differs between large and small animals. Thus, Timmers et al. (14) showed that inhibition of
cyclooxygenase (COX)-2, a cardioprotective protein in
ischemia-reperfusion and mediator of pre-conditioning in
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mice but also proinflammatory, results in impaired healing,
decreased infarct collagen, and increased LV rupture in pigs.
Third, healing in small animals such as mice (13) and rats
(15) is more rapid and remodeling is more severe than in
dogs (13,15) and humans (1), resulting in mature scar after
about 14 days in mice, 21 days in rats, 36 days to 42 days in
dogs, and 45 days to 180 days in humans (1).
Despite these clinically relevant species-dependent differences from studies in mice, such as the greater impairment
of mast-cell dependent repair (13), and propensity to LV
rupture (14) and the slower healing and remodeling (1) in
large animals after MI, mice are ideally suited for studies of
aging and healing post-MI. Such studies consistently show
impaired healing and/or repair, adverse remodeling, and
decreased survival in older mice (12,16). In fact, Gould et al.
(16) suggested that old mice (14 months) might be the
preferred model for post-MI congestive heart failure because they develop less effective repair and adverse remodeling with infarct expansion and septal hypertrophy,
whereas young mice (2 months) do not. Of note in that
study (16), captopril in the older mice improved survival and
limited hypertrophy (as in humans) but did not limit infarct
remodeling.
Four other points need emphasis. First, the shorter
lifespan of mice (Table 1) make longitudinal studies of
aging feasible, whereas similar studies in large animals are
prevented for logistic reasons and prohibitive cost. Second,
to place translational research studies in the clinical context,
from Table 1, a 2-year-old mouse would be equivalent to a
72-year-old human and a 2-month-old mouse to a 6-yearold human. Third, it is also important to note that temporally, both the march to necrosis and the march to scar
formation after MI are much abbreviated in mice compared
with large animals and humans. Fourth, most preclinical
studies in mice have been performed in young animals and
most clinical studies in adult rather than elderly humans (9),
although first MIs in humans occur in elderly persons.
Bujak et al. (12) do not provide data on antiinflammatory
agents, proof of cause-and-effect between defective healing
and adverse LV remodeling using genetic models, or the
regional distribution of several pertinent genes (e.g.,
SERCA2, phospholamban, and ANP). Nevertheless, their
finding of suppressed inflammatory and healing responses in
old mice (12) endorses the need for caution when using
Animal
and
Equivalence
Age, Life to
Expectancy,
Human Years
Animal Age, Life Expectancy,
Table 1
and Equivalence to Human Years
Life expectancy (yrs)
Equivalence (1 animal
yr to human yrs)
Mouse
Rat
Pig
Dog
2
4
10–15
20
34–38
30
39
7*
*10.5 dog yrs/human yr for the first 2 yrs, and 4 dog yrs/human yr thereafter. Data from
www.cbsnews.com/stories/2000/05/10/tech/main193799.shtml, www.futurepundit.com/
archives/002042.html [mouse]; www.ratbehavior.org/RatYears.htm [rat]; www.spfpig.com/data/
200608_Leaflet_E.pdf, www.findarticles.com/p/articles/mi_qn4155/is_20040905/
a i _ n 1 2 5 5 7 8 0 5 [ p i g ] ; w w w . o n l i n e c o n v e r s i o n . c o m / d o g y e a r s . h t m [ d o g ] ; www.
france-property-and-information.com/dog-years-to-human-years-age.htm.
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Jugdutt and Jelani
Editorial Comment
agents with anti-inflammatory effects in elderly patients
after reperfused MI and supports recent concerns raised by
the American Heart Association about the use of antiinflammatory agents after STEMI (17). Finally, the findings of Bujak et al. (12) have important implications for the
development of post-MI therapy in elderly persons.
Gradual reperfusion. The rate of reperfusion in animal
models (after release of ligatures or snares) is more abrupt than
in the human setting (after primary intervention or thrombolytic therapy). Post-conditioning (PC), consisting of brief
episodes of ischemia-reperfusion applied after sustained ischemia and before permanent reperfusion, provides gradual early
reperfusion that is cardioprotective. In contrast to classic
ischemic preconditioning, which must be applied before acute
MI and therefore is not clinically feasible, PC is an attractive
technique for reducing infarct size and is clinically applicable
after STEMI. Indeed, PC has been beneficial during percutaneous transluminal coronary angioplasty in human STEMI
patients, with a decrease in creatine kinase infarct size (18,19).
However, the average age was 58 years in the prospective study
(18) and 62 years in the retrospective study (19). Importantly,
these studies (18,19) provided proof that reperfusion injury
occurs in humans and PC is clinically feasible. The PC has
been effective in all animals tested except pigs. The mechanisms for the PC-induced myocardial salvage include the early
activation of classic survival kinase (i.e., the phosphatidylinositol-3-kinase– endothelial nitric oxide synthase–Akt;
extracellular-signal regulated kinase [ERK] 1/2) pathways as
well as early inhibition of the mitochondrial permeability
transition pore, oxidants, and inflammation. Akt (also called
Akt1 or protein kinase B), originally named after the viral
oncogene in the transforming retrovirus AKT8, is involved in
both survival and protein synthesis pathways. In fact, PC
attenuates most triggers of early reperfusion injury (i.e., cardiomyocyte and vascular endothelial apoptosis and necrosis,
oxidants, inflammatory cytokines, neutrophils, apoptotic
regulators).
In this issue of the Journal, Przyklenk et al. (20) provide
additional insight into the mechanism of aging-related attenuation of PC-mediated cardioprotection. Using an isolated
heart model with 30 min ischemia followed by abrupt reperfusion or PC (3 or 6 cycles of 10-s reperfusion and 10 s
ischemia before permanent reperfusion), they nicely show that
PC-induced limitation of infarct size seen in adult mice (3 to
4 months) is blunted in old mice (20 to 24 months). More
importantly, they show that this attenuation of cardioprotection in old mice is associated with similar increase in mitogenactivated protein kinase phosphatase-1 (MKP-1) as in adult
mice but a decrease in ERK 1/2 phosphorylation (rather than
an increase as found in adult mice). Additionally in old mice,
MKP inhibition with orthovanadate (PD98059) attenuated
the PC-induced increase in MKP-1, and restored the increase
in ERK and decrease in infarct size. Furthermore, PC did not
alter Akt in the young or old mice and the
phosphatidylinositol-3 kinase inhibitor LY294002 in supplementary studies did not block infarct size reduction (not
JACC Vol. 51, No. 14, 2008
April 8, 2008:1399–1403
shown). This suggests that the ERK pathway may be the main
survival pathway in PC. However, loss of PC-induced cardioprotection with aging was recently reported in signal transducer activator of transcription-3– deficient mice (21), suggesting that other signaling mechanisms might be involved in
elderly persons. It is pertinent that as in other PC studies,
Przyklenk et al. (20) did not find incremental benefit on LV
function compared with abrupt reperfusion. They also relied
on immunoblotting and did not establish cause and effect using
genetic models.
Future directions. There is a need to develop therapeutic
strategies that will optimize healing of the aging heart
wounded by a reperfused STEMI, with or without PC.
More studies are needed in elderly persons with STEMI,
with special focus on healing, and should include establishing the potential benefit of PC on long-term LV function,
remodeling, and outcome during healing and beyond.
Acknowledgment
The authors thank Catherine Jugdutt for assistance with
manuscript preparation.
Reprint requests and correspondence: Dr. Bodh I. Jugdutt,
2C2 Walter MacKenzie Health Sciences Centre, Division of
Cardiology, University of Alberta and Hospitals, 8440-112
Street, Edmonton, Alberta, T6G 2B7, Canada. E-mail:
[email protected].
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