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Corresponding author: Dr Susan E. Howlett, Department of Pharmacology, Dalhousie University, 5850 College St, PO Box 15000, Sir Charles Tupper Medical Building, Halifax, Nova Scotia B3H 4R2, Canada. Tel.: +1902-494-3552; fax: +1-902-494-1388.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, CanadaDepartment of Medicine (Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, CanadaInstitute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
The knowledge that advanced age is a major risk factor for cardiovascular disease (CVD) has stimulated interest in cardiac aging. Understanding how the heart remodels with age can help us appreciate why older individuals are more likely to acquire heart disease. Growing evidence in both humans and animals shows that the heart exhibits distinct structural and functional changes as a consequence of age. These changes occur even in the absence of overt cardiovascular disease and are often maladaptive. For example, atrial hypertrophy and fibrosis may increase susceptibility to atrial fibrillation in older adults. Age-dependent increases in left ventricular fibrosis, stiffness, and wall thickness promote diastolic dysfunction, predisposing to heart failure with preserved ejection fraction. The influence of age on the heart is evident at rest but is even more prominent during exercise. There is also evidence for sex-specific variation in age-associated remodelling. For instance, there is some evidence that the number of ventricular myocytes declines with age through apoptosis in men but not in women. This helps explain why older men are more likely than women to experience heart failure with reduced ejection fraction. Emerging evidence from preclinical studies suggests that frailty rather than chronological age promotes adverse cardiac remodelling. Mechanisms implicated in cardiac aging include impaired calcium handling, excessive activation of the ß-adrenergic and renin-angiotensin systems, and mitochondrial dysfunction. Further research into cardiac aging in both sexes is needed, because it may be possible to modify disease treatment if the substrate upon which the disease first develops is better understood.
Résumé
Sachant qu’un âge avancé constitue en soi un important facteur de risque de maladie cardiovasculaire (MCV), on s’intéresse actuellement de plus en plus au phénomène du vieillissement cardiaque. Une meilleure compréhension des mécanismes du remodelage cardiaque au fil du temps pourrait aider à expliquer pourquoi les personnes âgées sont plus susceptibles de souffrir de maladie du cœur. Des données probantes croissantes, obtenues tant chez des modèles animaux qu’humains, montrent que le cœur subit des modifications structurelles et fonctionnelles précises au fil des années. Ces modifications surviennent même en l’absence de MCV avérée et sont souvent la conséquence d’une problématique adaptative. Par exemple, l’hypertrophie et la fibrose auriculaire peuvent accroître le risque de fibrillation auriculaire chez les adultes plus âgés. De même, l’augmentation liée à l’âge de la fibrose, de la rigidité et de l’épaisseur de la paroi ventriculaire gauche peut favoriser l’apparition d’une dysfonction diastolique qui évoluera vers une insuffisance cardiaque sans altération de la fraction d’éjection ventriculaire gauche. Les effets de l’âge sur le cœur sont évidents au repos, mais plus encore à l’effort. Par ailleurs, des données montrent que le remodelage cardiaque s’effectue différemment en fonction du sexe. Par exemple, on sait désormais que le mécanisme d’apoptose entraîne une diminution du nombre de myocytes ventriculaires chez l’homme, mais pas chez la femme. Cela explique pourquoi les hommes sont plus susceptibles que les femmes de souffrir d’une insuffisance cardiaque avec réduction de la fraction d’éjection ventriculaire gauche. Des données probantes récentes, issues d’études précliniques, portent à croire que le remodelage cardiaque pathologique serait plus fonction de la fragilité de l’organisme que de l’âge chronologique de la personne. Parmi les mécanismes pathologiques impliqués dans le vieillissement cardiaque, on retrouve notamment les altérations du métabolisme calcique, l’activation excessive des systèmes ß-adrénergique et rénine-angiotensine ainsi que la dysfonction mitochondriale. Il faudra mener davantage de recherches sur le vieillissement cardiaque chez l’homme et la femme, car une meilleure compréhension des mécanismes sous-jacents permettrait sans doute de mieux adapter les stratégies de traitement des MCV.
The incidence of cardiovascular disease (CVD) rises dramatically with age in men and women. The idea that age itself is a risk factor for the development of CVD has motivated interest in the field of cardiac aging. Growing clinical and experimental evidence demonstrates that the aging process promotes structural and functional remodelling of the heart, even in the absence of overt CVD. Whether these age-related modifications represent a disease phenotype is debated. However, these changes do render the aging heart more susceptible to CVD, as discussed in detail in this review.
This article reviews important structural modifications in the aging heart at both the macroscopic and microscopic levels. We also discuss the impact of age on heart function, with emphasis on the pacemaker, the conduction system, the atria, and the ventricles. Key molecular mechanisms involved, including altered calcium homeostasis, dysregulation of the ß-adrenergic and renin-angiotensin pathways, and mitochondrial dysfunction are also considered. Throughout the review, we highlight male/female differences in cardiac aging. The terms “age” and “aging” are used to refer to the effect of chronological age on the heart, although we discuss emerging evidence that biological age, measured as frailty, may exacerbate changes associated with cardiac aging.
Age-Associated Changes in Cardiac Structure
Macroscopic changes associated with cardiac aging
Normal cardiac aging is characterized by structural changes at both macroscopic and microscopic levels. Studies in humans have shown that epicardial adipose tissue deposition increases markedly with age.
In addition, there are changes in the gross morphologic structure of the heart. Atrial remodelling characterized by larger atrial size and volume occurs, although not until the eighth decade unless underlying CVD is present.
although LV mass-to-volume ratios increase with age in both men and women. The major macroscopic changes in heart structure with age are illustrated in Figure 1.
Figure 1Major age-dependent changes in the structure of the heart at the macroscopic and microscopic levels. (A) Young adult heart. (B) Aged heart. Compared with the younger adult heart, the aged heart exhibits gross structural changes, including epicardial fat deposition, calcification of the aortic valve, atrial hypertrophy and dilatation, as well as hypertrophy of the left ventricle. Changes at the cellular level include the loss of ventricular myocytes and hypertrophy of the remaining cells. There is also an increase in the number of fibroblasts with age and a marked increase in fibrosis. Some of these age-dependent changes may be modified by factors such as sex and frailty, as discussed in the text. Illustration by Monique Guilderson.
Reproduced with permission of Maritime Medical Design and Monique Guilderson.
Age-dependent cardiac remodelling also occurs at the microscopic level. In humans, the number of sinoatrial node (SAN) pacemaker cells declines markedly with age.
Age-related cell loss can, in theory, increase the mechanical burden on surviving myocytes and lead to compensatory hypertrophy. Morphometric analysis suggests that ventricular myocyte volume increases with age and that this may be more pronounced in men than in women.
Still, the question of whether age-dependent myocyte loss and hypertrophy occur at different rates and through different mechanisms in male and female hearts has not been firmly established, and additional studies would be helpful in resolving this issue. Although the number of cardiomyocytes may decline with age, there is marked proliferation of cardiac fibroblasts, the cells that produce extracellular matrix and collagen.
Key microscopic changes characteristic of cardiac aging are shown in Figure 1. Both gross and cellular changes in heart structure with age are believed to adversely affect myocardial function, as discussed in detail in the section Impact of Age on Cardiac Function.
Animal models exhibit the major age-associated structural changes seen in humans
Animal models have been used to explore many aspects of cardiac aging. Rats and mice have a 50% mortality rate at 24 months of age,
so most studies use 24-month-old rodents to model human aging. Many of the macroscopic changes characteristic of aging human hearts also occur in older animals. For example, epicardial fat deposition and aortic valve calcification are seen in older animals.
Microscopic changes observed in aging human hearts are also seen in older animals. Whether the number of pacemaker cells decreases with age in animals is unclear, but the expression of ion channels involved in SAN function declines with age in rats.
Ventricular myocyte loss through apoptosis, along with an increase in the cross-sectional area of surviving cells, occurs in aging male nonhuman primates, although this is not seen in older female nonhuman primates.
There also is a growing consensus that ventricular myocyte hypertrophy (increased length, width, and cross-sectional area) occurs in aging male rodents as well as in guinea pigs and rabbits.
Whether ventricular myocyte hypertrophy occurs in myocytes from female aging rodents is less clear because some studies have reported increased cell length, width, and area, whereas others have not.
This suggests that both concentric hypertrophy, associated with lateral growth of individual myocytes, and eccentric hypertrophy, linked to longitudinal cell growth, may occur in the aging male heart. As with humans, additional studies that investigate whether age-dependent myocyte loss and hypertrophy occur at the same rates and through the same mechanisms in both sexes would be interesting. Other age-dependent cellular changes reported in aging rodents and in larger animals include fibroblast proliferation, collagen accumulation, and interstitial fibrosis in both the atria and the ventricles.
Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants.
Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants.
Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial.
Our group has explored the link between biological age, measured as frailty, and age-dependent changes in the heart. We developed a method to quantify frailty with a “frailty index” based on the idea that health deficits accumulate with age.
A frailty index score is obtained by counting the deficits in health in an individual and dividing by the total number of potential deficits to obtain a score between 0 (no deficits) and 1 (all possible deficits). Our work has shown that myocyte hypertrophy occurs predominantly in aged mice with high frailty scores.
Thus, some aspects of age-dependent remodelling might be more closely linked to biological age (frailty) than chronological age.
Impact of Age on Cardiac Function
Many structural changes associated with normal aging are maladaptive. For example, age-related increases in epicardial adipose tissue are associated with a higher prevalence of various CVDs,
although whether pericardial adipose tissue increases with age is unclear. This could be important, because pericardial fat is a known risk factor for diseases such as atrial fibrillation, which is common in older adults.
The concept that age adversely affects heart structure and predisposes elderly individuals to acquire heart disease has encouraged interest in the effects of age on electrical and contractile function of the heart.
Influence of age on pacemaker and cardiac conduction processes
Heart rate (HR) is not affected by age in supine men and women.
Medrano G, Hermosillo-Rodriguez J, Pham T, et al. Left atrial volume and pulmonary artery diameter are noninvasive measures of age-related diastolic dysfunction in mice [e-pub ahead of print]. J Gerontol A Biol Sci Med Sci 2015, accessed November 24, 2015.
Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.
as discussed in the section The Impact of Age on Heart Function During Exercise. A decline in pacemaker cell number and reduced ion channel expression in SAN cells may diminish automaticity and contribute to lower HRs in older adults.
The cardiac conduction system changes characteristically with age. Age-related prolongation of the QRS complex, consistent with a slowing of conduction, is seen in humans and animals.
Bonda TA, Szynaka B, Sokołowska M, et al. Remodeling of the intercalated disc related to aging in the mouse heart [e-pub ahead of print]. J Cardiol http://dx.doi.org/10.1016/j.jjcc.2015.10.001, accessed December 14, 2015.
Bonda TA, Szynaka B, Sokołowska M, et al. Remodeling of the intercalated disc related to aging in the mouse heart [e-pub ahead of print]. J Cardiol http://dx.doi.org/10.1016/j.jjcc.2015.10.001, accessed December 14, 2015.
These age-dependent changes in conduction may promote dysrhythmias in older adults.
Age-dependent atrial remodelling
In young adults, early LV filling occurs rapidly so that very little filling is caused by atrial contraction later in diastole. By contrast, slow early LV filling is a characteristic feature of the aging heart, as discussed in more detail in the section Diastolic Dysfunction. Slow LV filling increases diastolic filling pressure, which results in atrial dilatation and hypertrophy.
In consequence, the atria make a larger contribution to ventricular filling in older adults than in younger adults. Thus, attenuation of atrial contraction in diseases such as atrial fibrillation can markedly reduce diastolic volumes in older individuals.
This reduces cardiac output, which predisposes older individuals toward the development of heart failure.
Dilatation is not the only change in aging atria. Along with the loss of SAN cells, there is a loss of atrial myocytes and increased interstitial fibrosis.
Mechanisms implicated in cardiac fibrosis include chronic systemic activation of the renin-angiotensin-aldosterone system, mitochondrial dysfunction, and generation of reactive oxygen species,
as discussed in the section Cellular Mechanisms of Dysfunction in the Aging Heart.
Other studies have investigated age-dependent changes in atrial electrophysiology. Most studies have used atrial myocytes from patients with underlying CVD, and few have examined individuals older than 70 years of age.
Thus, whether age influences the electrophysiological properties of atrial myocytes from healthy older humans is not clear. Studies in older animals have shown that right atrial myocytes are depolarized, with longer action potentials than those in younger animals.
These changes in action potential configuration are associated with an increase in potassium currents, although calcium currents in these cells decline with age.
Together, age-related changes in ion channels, along with atrial fibrosis and hypertrophy, provide an ideal substrate for the development of atrial fibrillation, which is common in older adults.
There is evidence for a higher incidence of atrial fibrillation in men, although women often have worse outcomes, including stroke and systemic embolization.
Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants.
Whether age-dependent atrial remodelling differs between the sexes is not yet clear, and additional studies are warranted.
Age and sex affect resting systolic function
Traditionally, measures of systolic function, including stroke volume and ejection fraction, were said to be similar in young and older adults at rest.
Interestingly, echocardiographic studies in animals support this view. Systolic function (stroke volume, ejection fraction) declines with age in male rodents but not in female rodents.
Medrano G, Hermosillo-Rodriguez J, Pham T, et al. Left atrial volume and pulmonary artery diameter are noninvasive measures of age-related diastolic dysfunction in mice [e-pub ahead of print]. J Gerontol A Biol Sci Med Sci 2015, accessed November 24, 2015.
Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.
Corresponding changes occur at the cellular level. There is some evidence from studies in both humans and animals that the number of ventricular myocytes declines with age in the male but not the female sex.
Furthermore, our work in rodents has shown that the ability of ventricular myocytes to contract declines with age in male rodents more than in female rodents.
Frailty also appears to affect contractile function in older adults. We have found that cellular contractile depression occurs in mice with the highest frailty scores, whereas those with lower scores show little evidence of contractile dysfunction.
This is important because frailty is common in older patients with heart failure, who experience worse outcomes and higher mortality than do nonfrail patients of the same age.
That frailty predicts contractile dysfunction better than does chronological age suggests that frailty may predispose individuals toward the development of heart failure.
Diastolic dysfunction, characterized by problems with relaxation, is a hallmark of cardiac aging. In young adult hearts, LV filling occurs early and rapidly as a consequence of ventricular relaxation.
This age-dependent slowing of relaxation in diastole may predispose the aging heart toward heart failure with preserved ejection fraction, commonly referred to as HFpEF.
Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.
Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial.
Risk factors for HFpEF also differ between the sexes, with factors such as myocardial ischemia being important in men and hypertension playing a major role in women.
The increase in diastolic dysfunction with age is significant, because population aging has led to a growing epidemic of HFpEF. Furthermore, although evidence-based treatments can improve prognosis in HFrEF, there are no current treatments for HFpEF.
The increasing prevalence and lack of treatment options for HFpEF has promoted interest in the determinants of age-related diastolic dysfunction. Aging rodents of both sexes exhibit slowed relaxation and diastolic dysfunction.
Medrano G, Hermosillo-Rodriguez J, Pham T, et al. Left atrial volume and pulmonary artery diameter are noninvasive measures of age-related diastolic dysfunction in mice [e-pub ahead of print]. J Gerontol A Biol Sci Med Sci 2015, accessed November 24, 2015.
Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.
This suggests that underlying mechanisms of potential relevance to humans can be investigated in animals. Several mechanisms have been implicated. For example, increased fibrosis is thought to increase ventricular stiffness.
In addition, increased myocyte stiffness, mediated by age-dependent changes in the sarcomeric protein titin, contribute to the increase in LV stiffness in HFpEF.
Changes in intracellular calcium homeostasis have also been implicated in the pathogenesis of HFpEF, as discussed in the section Cellular Mechanisms of Dysfunction in the Aging Heart.
The impact of age on cardiac function during exercise
The effects of cardiac aging are seen more clearly during exercise when the heart must respond to stress. Although resting HRs are not affected by age, the maximum HR achieved during exercise declines with age in both sexes.
Reduced sensitivity of the myocardium to sympathetic stimulation is implicated. Normally, activation of the sympathetic nervous system during exercise releases catecholamines (eg, noradrenaline, adrenaline) that activate β-adrenergic receptors in the heart to increase the rate and force of contraction. However, the evidence that the heart's responsiveness to β-adrenergic stimulation declines with age in humans and animals is strong,
The age-related decrease in catecholamine sensitivity is mediated by ß1-adrenergic receptors linked to a decrease in adenylate cyclase activity in ventricular myocytes from male Fischer 344 rats.
as discussed in the section Intracellular Calcium Homeostasis. Interestingly, 1 study in nonhuman primates found that in vivo responses to β-adrenergic receptor stimulation declined with age in the male but not the female sex.
Still, whether responsiveness to catecholamines differs between the sexes is unclear, because most clinical/preclinical studies have either focused on older male animals or have not investigated sex differences.
Because HR is a key determinant of cardiac output, a lower maximum HR is thought to impair the ability of the aging heart to augment cardiac output during exercise.
The age-dependent decrease in sensitivity to β-adrenergic stimulation also directly limits the increase in contractile force in response to exercise in older adults.
The age-related decrease in catecholamine sensitivity is mediated by ß1-adrenergic receptors linked to a decrease in adenylate cyclase activity in ventricular myocytes from male Fischer 344 rats.
This produces more blood in the ventricle at the end of diastole, which through the Frank-Starling mechanism increases stretch on the heart and the strength of contraction. Greater reliance on the Frank-Starling mechanism may at least partially compensate for the lower HR and reduced contractility of the aging heart during exercise.
The major structural and functional changes associated with cardiac aging, along with potential clinical consequences and important sex differences, are summarized in Table 1.
Cellular Mechanisms of Dysfunction in the Aging Heart
Animal models have yielded evidence for a variety of molecular mechanisms that contribute to structural and functional remodelling of the aging heart. A full consideration of the mechanisms implicated in cardiac aging is beyond this review's remit. We focus on altered calcium homeostasis, chronic systemic activation of the β-adrenergic and renin-angiotensin pathways, and mitochondrial dysfunction as likely mechanisms in key aspects of cardiac aging.
Intracellular calcium homeostasis
Cardiac contraction and relaxation reflect the rise and fall of intracellular calcium levels in individual cardiac myocytes. Age-dependent changes in the regulation of intracellular calcium affect the ability of the heart to contract.
For example, smaller calcium transients are responsible for the smaller contractions observed in ventricular myocytes from aged male rodents compared with younger animals.
Smaller calcium transients are thought to arise, in part, from a reduction in peak calcium currents, leading to less calcium influx in myocytes from aged male rodents.
By contrast, age has little effect on peak calcium transients, calcium currents, or contractions in cells from female rodents and actually enhances these responses in cells from aged sheep.
The age-dependent decrease in peak calcium transients/contractions in myocytes from male animals but not female animals may help explain why systolic dysfunction and HFrEF are seen more in older men than in older women.
Altered calcium homeostasis also helps explain slowed relaxation and diastolic dysfunction in the aging heart. Prolongation of relaxation in the aging heart reflects a slower rate of decay of the calcium transient.
Slower calcium transient decay arises from reduced calcium uptake into stores in the sarcoplasmic reticulum (SR), resulting from reduced expression and activity of the SR calcium–adenosine triphosphatase pump.
Prolonged availability of internal calcium causes persistent activation of contractile filaments, which delays active ventricular relaxation and compromises LV filling in early diastole.
Still, why HFpEF occurs more commonly in women, whereas outcomes are worse in men, obliges further investigations.
Chronic activation of the β-adrenergic and renin-angiotensin pathways
Normally, activation of cardiac β-adrenergic receptors increases HR and contractile force, but there is strong evidence that myocardial responsiveness to β-adrenergic stimulation declines with age.
This age-related decline in sensitivity to catecholamine stimulation has been attributed to high levels of circulating catecholamines, which lead to chronic activation of the β-adrenergic pathway in humans and animals.
Chronic activation of this pathway arises from reduced plasma clearance of noradrenaline and increased catecholamine spillover into circulation from organs such as the heart.
Chronic activation of the β-adrenergic pathway has been implicated in several aspects of cardiac aging. For example, chronic β-adrenergic stimulation can damage the heart by increasing the production of mitochondrial reactive oxygen species (ROS),
as discussed in the section Mitochondrial Dysfunction. It also can desensitize elements of the β-adrenergic signalling cascade and limit the increased HR response seen with changing position or with exercise.
The underlying mechanisms have not been fully elucidated, but there is evidence that fewer β-adrenergic receptors, less cyclic adenosine monophosphate production or desensitization of other components of the β-adrenergic signalling pathway (or a combination) play a role.
The age-related decrease in catecholamine sensitivity is mediated by ß1-adrenergic receptors linked to a decrease in adenylate cyclase activity in ventricular myocytes from male Fischer 344 rats.
few studies have directly compared older men and women. Additional studies in humans and animal models could clarify this issue.
Chronic activation of the renin-angiotensin system also is thought to play a role in cardiac aging. In younger animals, chronic infusion of angiotensin II causes cardiac hypertrophy, fibrosis, and slowed relaxation,
a phenotype that resembles cardiac aging. Studies have shown that activation of angiotensin II type 1 receptors on fibroblasts stimulates fibroblast proliferation, increases collagen synthesis, and augments the expression of extracellular matrix proteins.
Angiotensin II is also thought to promote growth in adult cardiac myocytes by inducing the expression of growth factors such as transforming growth factor β.
as discussed in the section Mitochondrial Dysfunction. These similarities between the angiotensin II–treated heart and the aging heart suggest that angiotensin II may play a role in cardiac aging. Indeed, evidence from rodent models has shown that cardiac angiotensin II levels increase with age, and this has been linked to hypertrophy, fibrosis, and diastolic dysfunction in the aging heart.
Interestingly, the effects of angiotensin on the aging heart appear to differ between the sexes. For example, female mice with elevated intracardiac levels of angiotensin II exhibit age-dependent contractile depression, whereas male mice do not.
These findings support the concept that the influence of age on the heart differs prominently between the sexes.
Mitochondrial dysfunction
The heart is rich in mitochondria that help provide the energy required for optimal myocardial function. Conversely, mitochondrial respiration is a major source of ROS production, so high levels of these organelles in the heart increase its risk of oxidative damage.
Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging.
It is currently thought that the age-associated increase in mitochondrial ROS damages mitochondrial DNA, which disrupts mitochondrial function, further increasing ROS production and damaging mitochondrial DNA plus other macromolecules.
The key role of ROS generation and mitochondrial dysfunction in cardiac aging is supported by experiments that target mitochondrial ROS. For example, overexpression of the ROS scavenger enzyme catalase attenuates the development of hypertrophy, fibrosis, and diastolic dysfunction in the aging mouse heart.
By contrast, prematurely aging mice with a mutation in mitochondrial DNA polymerase exhibit marked cardiac hypertrophy and fibrosis as well as systolic and diastolic dysfunction.
Together, these observations suggest that ROS generation and mitochondrial damage contribute to cardiac aging. Still, the role of ROS accumulation in aging is controversial because some studies suggest that intracellular ROS may also have beneficial effects in aging,
Much of the research reviewed here has focused on a small number of mechanisms in the context of aging changes. Many studies have only used males of the species in the belief (generally false)
that the estrus cycle gives too great a degree of variability for valid conclusions about the impact of age. Ironically, much less attention has been paid to the well-recognized variability in degree of age-related changes in animals of the same age,
clearly contribute to sex differences in CVD expression. In addition, as reviewed here, there are marked age-dependent changes in the structure and function of the heart that differ between the sexes. This cardiac remodelling occurs even in healthy older adults with no signs of overt CVD. Still, whether cardiac aging itself represents a disease is debated. Sir John Grimley Evans once said that “to draw a distinction between disease and normal aging is to attempt to separate the undefined from the indefinable.”
in part because many of its adverse effects can be modified by factors such as changes in diet and exercise. Although the relationship between cardiac aging and heart disease may be contested, there is little doubt that age-associated structural and functional changes in the heart have potentially important clinical consequences, as summarized in Table 1. Table 1 also indicates that many features of cardiac aging differ between the sexes, although more work in this area is clearly needed. There is emerging evidence that frailty may have a major impact on cardiac aging, an idea that is motivating additional research by our group. An improved understanding of the mechanisms involved in the effects of age and frailty on both male and female hearts may help explain why men and women are susceptible to different CVDs as they age and may help identify new treatments for these diseases in both sexes.
Acknowledgements
The authors express their appreciation for the artwork created by Monique Guilderson of Maritime Medical Design.
Funding Sources
This study was supported by grants from the Canadian Institutes for Health Research (MOP 126018 and MOP 97973).
Disclosures
The authors have no conflicts of interest to disclose.
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Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy.
Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants.
Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial.
Medrano G, Hermosillo-Rodriguez J, Pham T, et al. Left atrial volume and pulmonary artery diameter are noninvasive measures of age-related diastolic dysfunction in mice [e-pub ahead of print]. J Gerontol A Biol Sci Med Sci 2015, accessed November 24, 2015.
Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.
Bonda TA, Szynaka B, Sokołowska M, et al. Remodeling of the intercalated disc related to aging in the mouse heart [e-pub ahead of print]. J Cardiol http://dx.doi.org/10.1016/j.jjcc.2015.10.001, accessed December 14, 2015.
The age-related decrease in catecholamine sensitivity is mediated by ß1-adrenergic receptors linked to a decrease in adenylate cyclase activity in ventricular myocytes from male Fischer 344 rats.
Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging.
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