Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy

https://doi.org/10.1016/j.exger.2011.02.010Get rights and content

Abstract

Aging is associated with an increased incidence of heart failure, but the existence of an age-related cardiomyopathy remains controversial. Differences in strain, age and technique of measuring cardiac function differ between experiments, confounding the interpretation of these studies. Additionally, the structural and genetic profile at the onset of heart failure has not been extensively studied. We therefore performed serial echocardiography, which allows repeated assessment of left ventricular (LV) function, on a cohort of the same mice every 3 months as they aged and demonstrated that LV systolic dysfunction becomes apparent at 18 months of age. These aging animals had left ventricular hypertrophy and fibrosis, but did not have inducible ventricular tachyarrhythmias. Gene expression profiling of left ventricular tissue demonstrated 40 differentially expressed probesets and 36 differentially expressed gene ontology terms, largely related to inflammation and immunity. At this early stage of cardiac dysfunction, we observed increased cardiomyocyte expression of the pro-apoptotic activated caspase-3, but no actual increase in apoptosis. The aging hearts also have higher levels of anti-apoptotic and autophagic factors, which may have rendered protection from apoptosis. In conclusion, we describe the functional, structural and genetic changes in murine hearts as they first develop cardiomyopathy of aging.

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.

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