Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy
Research Highlights
► Aging murine hearts develop hypertrophy, fibrosis and systolic dysfunction by 18 months. ► Microarray analysis reveals increase in inflammatory and immune-related genes. ► Parallel increases in pro- and anti-apoptotic factors cause no change in cardiomyocyte apoptosis.
Introduction
Heart failure affects approximately 5.7 million Americans (NIH, 2008) at an estimated annual cost of $37 billion (Lloyd-Jones et al., 2009). Aging is associated with a dramatic increase in the incidence and prevalence of heart failure: heart failure is four-times more common in those over 85 years, compared to those aged 65–74 years (Lloyd-Jones et al., 2009). As our population continues to age (DHHS, 2008), the burden of heart failure will increase.
The effect of aging on contractile function of the heart remains controversial. Some have demonstrated overt systolic dysfunction with age (Biesiadecki et al., 2010, Inuzuka et al., 2009, Peart and Gross, 2004), but others have not (Barouch et al., 2003, Bujak et al., 2008, Ma et al., 2010, Sato et al., 2003). Still other groups have shown that aging is associated with normal baseline cardiac function, but reduced cardiac response to inotropic stimuli (Folkow and Svanborg, 1993, Lakatta and Sollott, 2002). However, even among those who have demonstrated an age-related cardiomyopathy, the age at which it occurs is still a matter of some debate. Furthermore, the gene transcription profile of the aging heart and the contributions of cardiomyocyte apoptosis and autophagy to the cardiomyopathy of aging have not been fully described. To describe and quantify these pathologies is the first step toward developing disease-specific approaches to the treatment of age-related cardiomyopathy. There may be reversible steps during the development of age-related cardiomyopathy, where interventions could prevent progression to heart failure. Any such treatment would have the potential to improve longevity and quality of life for millions of people each year, and provide significant savings for health-care budgets.
To confirm the presence of age-related contractile cardiomyopathy, and to most accurately describe its age of onset, we followed mice with serial echocardiography as they aged to determine the age at which they first developed systolic dysfunction, and we found this occurred long before they were senescent or dying. The median life expectancy of male C57Bl6 mice is approximately 30 months (Yuan et al., 2009), but we found the development of systolic dysfunction by 18 months. We termed this “aging” rather than “old” or “senescent”, and we focused our studies of cardiac structure, function and gene profile at this age.
Section snippets
Animals and study groups
Male C57BL/6J were used for all experiments. Young mice were 2 months old and aging mice were 18 months old. Animals were handled according to the guidelines of the Institutional Animal Care and Use Committee at the University of California San Francisco.
Echocardiography
Echocardiography was accomplished under isoflurane anesthesia with the use of a Vevo660 (VisualSonics, Toronto, Canada) equipped with a 30-MHz transducer as previously described (Yeghiazarians et al., 2009). Echocardiograms were obtained at 12,
Systolic contractile dysfunction occurs at 18 months of age
Serial echocardiography was performed on a cohort of aging mice. By 18-months of age, mice exhibit impairment of left ventricular systolic function. Echocardiographic and weight data are presented in Fig. 1 and Table 1.
Increased interstitial fibrosis and hypertrophy in aging hearts
Aged hearts displayed a significant increase in fibrosis; in particular, collagen levels were increased compared to young animals (Fig. 2). In addition to the increased myocardial fibrosis, aged hearts display cardiomyocyte hypertrophy. This phenotype resembles hypertensive heart
Discussion
With serial assessment of left ventricular function in a cohort of mice, we have described the age at which mice develop systolic dysfunction, and focused our tissue analysis on this timepoint. We have demonstrated that aging male C57/Bl6 mice: 1) develop contractile dysfunction at 18 months of age, and this is associated with structural changes of increased fibrosis and cardiomyocyte hypertrophy; 2) have a different gene expression profile in the left ventricular myocardium from young mice with
Acknowledgments
This study was funded by the Ellison Medical Foundation and the National Institutes of Health. We are grateful to Jinny Wong for the assistance with electron microscopy and Philip Ursell, MD for the assistance with histology.
References (39)
- et al.
Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice
Journal of Molecular and Cellular Cardiology
(2003) - et al.
Correlation between mast cell density and myocardial fibrosis in congestive heart failure patients
Transplantation Proceedings
(2007) - et al.
Removal of the cardiac troponin I N-terminal extension improves cardiac function in aged mice
The Journal of Biological Chemistry
(2010) - et al.
Transition from compensated hypertrophy to systolic heart failure in the spontaneously hypertensive rat: structure, function, and transcript analysis
Genomics
(2010) - et al.
Aging-Related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction
Journal of the American College of Cardiology
(2008) - et al.
CCR2 regulates monocyte recruitment as well as CD4+ Th1 allorecognition after lung transplantation
American Journal of Transplantation
(2010) - et al.
Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death
Journal of Molecular and Cellular Cardiology
(2008) - et al.
Perspectives on mammalian cardiovascular aging: humans to molecules
Comparative Biochemistry and Physiology. Part A: Molecular & Integrative Physiology
(2002) - et al.
Autophagy in the pathogenesis of disease
Cell
(2008) - et al.
Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle
Mechanisms of Ageing and Development
(2010)
Signalling and autophagy regulation in health, aging and disease
Molecular Aspects of Medicine
Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts
Experimental Gerontology
Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex
Current Opinion in Immunology
The late phase of ischemic preconditioning induces a prosurvival genetic program that results in marked attenuation of apoptosis
Journal of Molecular and Cellular Cardiology
Time course of the apoptotic cascade and effects of caspase inhibitors in adult rat ventricular cardiomyocytes
Journal of Molecular and Cellular Cardiology
Age-related changes in ischemic tolerance in male and female mouse hearts
Journal of Molecular and Cellular Cardiology
Injection of bone marrow cell extract into infarcted hearts results in functional improvement comparable to intact cell therapy
Molecular Therapy
Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart
Physiological Genomics
The role of inflammatory and fibrogenic pathways in heart failure associated with aging
Heart Failure Reviews
Cited by (118)
The link between obesity and aging - insights into cardiac energy metabolism
2023, Mechanisms of Ageing and DevelopmentNT-proBNP point-of-care measurement as a screening tool for heart failure and CVD risk in type 2 diabetes with hypertension
2023, Journal of Diabetes and its ComplicationsMuscle-specific programmed cell death 5 deletion attenuates cardiac aging
2021, International Journal of CardiologyEffects of obesity on the cardiac proteome
2021, Endocrine and Metabolic ScienceTransthoracic Ultrasound Improves Cardiac Function in Mice
2024, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency ControlSilencing of UTX Mitigates Aging-Associated Cardiac Fibrosis via Blocking Cardiac Fibro blaststo- Myofi brobl asts Trans-Differentiation
2023, Anatolian Journal of Cardiology