Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse

Abstract

heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 Ϯ 0.03 in SAMR1 mice to 1.2 Ϯ 0.03 in SAMP8 mice (P Ͻ 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 Ϯ 0.9 mm/s in SAMR1 to 21.1 Ϯ 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 Ϯ 0.02 to 0.8 Ϯ 0.03 in SAMR1 vs. SAMP8 mice, respectively (P Ͻ 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 Ϯ 0.05 vs. 0.8 Ϯ 0.14; P Ͻ 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 Ϯ 0.04 to 0.8 Ϯ 0.09% and perivascular collagen area increased from 1.0 Ϯ 0.11 to 1.6 Ϯ 0.14%. Transforming growth factor-␤ and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P Ͻ 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies. heart failure; transforming growth factor; aging HEART FAILURE IS A MAJOR AND growing public health concern in the United States; there are an estimated 5 million people living with this disease, and another 550,000 patients will be diagnosed yearly (6). Approximately one-half of all heart failure patients in the United States suffer from diastolic heart failure, and it is a major cause of mortality in the elderly population (35). Diastolic heart failure describes a group of patients whose clinical manifestation of congestive heart failure is characterized by normal left ventricular diastolic volume, a normal ejection fraction, delayed active relaxation, and increased passive stiffness of the left ventricle (34). Diastolic dysfunction precedes diastolic heart failure and is often clinically silent; it is characterized by abnormal ventricular distensibility, relaxation, and filling (1). Both diastolic dysfunction and diastolic heart failure are most common in the elderly population. In a study that examined the prevalence of this form of heart failure, 50% of patients over the age of 70 showed evidence of diastolic heart failure. Studies (35) indicate that the most important determinants for development of diastolic dysfunction and diastolic heart failure are age and hypertension. Although the exact molecular mechanisms behind diastolic dysfuncti...

Impaired Left Ventricular Filling in COPD and Emphysema: Is It the Heart or the Lungs?

“…Further, there is evidence to support accelerated aging in the pathogenesis of COPD and emphysema 49,50 and similar mechanisms have been proposed for diastolic dysfunction. 51,52 In addition, LV myocardial fi brosis has been demonstrated in patients with COPD and cor pulmonale. 53 There are several limitations to the current study.…”

The Aging Heart: Figure 1.

“…Mice overexpressing CTGF in a cardiomyocyte-specific manner show accelerated cardiac aging and begin to develop age-related cardiac dysfunction at 7 mo of age (Panek et al 2009). The role of ECM synthesis in cardiac aging is also implicated by the accelerated myocardial fibrosis that accompanies higher TGF-b and CTGF levels in senescence-accelerated mice that display diastolic dysfunction at 6 mo of age (Reed et al 2011). In another study, Bradshaw et al (2010) showed that expression of a matricellular protein, secreted protein acidic and rich in cysteine (SPARC), increased with age, and that deletion of SPARC resulted in reduced fibrillar collagen content in the LV and decreased LV diastolic stiffness.…”

Rodent models of heart failure: an updated review

“…Despite the great difficulty in developing an animal model of DHF age-induced, a recent study has characterized a model demonstrating isolated diastolic dysfunction associated with accelerated aging [235]. This mouse model is a spontaneous senescence model that displays many common geriatric disorders in the human population and recapitulates diastolic dysfunction as it naturally occurs in the elderly.…”

“…This suggests that the physiologic abnormality manifests over a relatively short period of time and, from an experimental standpoint, adds an advantage as it allows for a more rapid study of pathophysiologic mechanisms. The senescence-accelerated mouse model will probably turn to be a useful model for future studies of age-related diastolic dysfunction, since the better insight into its underlying mechanisms could pave the way for designing specific pharmacologic strategies to prevent or treat this pathology [235].…”