The impact of age and frailty on ventricular structure and function in C57BL/6J mice.

Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to the same extent, in all older individuals. That aging happens at different rates is well accepted clinically. People who are aging rapidly are frail and frailty is measured with a 'frailty index'. We quantified frailty with a validated mouse frailty index tool and evaluated the impacts of age and frailty on cardiac hypertrophy and contractile dysfunction. Hypertrophy increased with age, while contractions, calcium currents and calcium transients declined; these changes were graded by frailty scores. Overall health status, quantified as frailty, may promote maladaptive changes associated with cardiac aging and facilitate the development of diseases such as heart failure. To understand age-related changes in heart structure and function, it is essential to know both chronological age and the health status of the animal. On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodelling. Frailty was quantified as deficit accumulation in adult (≈7 months) and aged (≈27 months) C57BL/6J mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r = 0.67-0.55, P < 0.0003). Myocyte area also correlated positively with FI (r = 0.34, P = 0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r = -0.51, P = 0.0007; r = -0.48, P = 0.002; r = -0.56, P = 0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r = -0.40, P = 0.008), lower gain (r = -0.37, P = 0.02) and reduced expression of Cav1.2 protein (r = -0.68, P = 0.003). These results show that cardiac hypertrophy and contractile dysfunction in naturally aging mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac aging.

Feridooni HA ，Kane AE ，Ayaz O ，Boroumandi A ，Polidovitch N ，Tsushima RG ，Rose RA ，Howlett SE ... -  《-》

Caveolin 3-dependent loss of t-tubular I(Ca) during hypertrophy and heart failure in mice.

What is the central question of this study? Heart failure is associated with redistribution of L-type Ca2+ current (ICa ) away from the t-tubule membrane to the surface membrane of cardiac ventricular myocytes. However, the underlying mechanism and its dependence on severity of pathology (hypertrophy versus failure) are unclear. What is the main finding and its importance? Increasing severity of response to transverse aortic constriction, from hypertrophy to failure, was accompanied by graded loss of t-tubular ICa and loss of regulation of ICa by caveolin 3. Thus, the pathological loss of t-tubular ICa , which contributes to impaired excitation-contraction coupling and thereby cardiac function in vivo, appears to be attributable to loss of caveolin 3-dependent stimulation of t-tubular ICa . Previous work has shown redistribution of L-type Ca2+ current (ICa ) from the t-tubules to the surface membrane of rat ventricular myocytes after myocardial infarction. However, whether this occurs in all species and in response to other insults, the relationship of this redistribution to the severity of the pathology, and the underlying mechanism, are unknown. We have therefore investigated the response of mouse hearts and myocytes to pressure overload induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or equivalent sham operation 8 weeks before use. ICa and Ca2+ transients were measured in isolated myocytes, and expression of caveolin 3 (Cav3), junctophilin 2 (Jph2) and bridging integrator 1 (Bin1) was determined. C3SD peptide was used to disrupt Cav3 binding to its protein partners. Some animals showed cardiac hypertrophy in response to TAC with little evidence of heart failure, whereas others showed greater hypertrophy and pulmonary congestion. These graded changes were accompanied by graded cellular hypertrophy, t-tubule disruption, decreased expression of Jph2 and Cav3, and decreased t-tubular ICa density, with no change at the cell surface, and graded impairment of Ca2+ release at t-tubules. C3SD decreased ICa density in control but not in TAC myocytes. These data suggest that the graded changes in cardiac function and size that occur in response to TAC are paralleled by graded changes in cell structure and function, which will contribute to the impaired function observed in vivo. They also suggest that loss of t-tubular ICa is attributable to loss of Cav3-dependent stimulation of ICa .

Bryant SM ，Kong CHT ，Watson JJ ，Gadeberg HC ，James AF ，Cannell MB ，Orchard CH ... -  《-》

The impacts of age and frailty on heart rate and sinoatrial node function.

Sinoatrial node (SAN) function declines with age; however, not all individuals age at the same rate and health status can vary from fit to frail. Frailty was quantified in young and aged mice using a non-invasive frailty index so that the impacts of age and frailty on heart rate and SAN function could be assessed. SAN function was impaired in aged mice due to alterations in electrical conduction, changes in SAN action potential morphology and fibrosis in the SAN. Changes in SAN function, electrical conduction, action potential morphology and fibrosis were correlated with, and graded by, frailty. This study shows that mice of the same chronological age have quantifiable differences in health status that impact heart rate and SAN function and that these differences in health status can be identified using our frailty index. Sinoatrial node (SAN) dysfunction increases with age, although not all older adults are affected in the same way. This is because people age at different rates and individuals of the same chronological age vary in health status from very fit to very frail. Our objective was to determine the impacts of age and frailty on heart rate (HR) and SAN function using a new model of frailty in ageing mice. Frailty, which was quantified in young and aged mice using a frailty index (FI), was greater in aged vs. young mice. Intracardiac electrophysiology demonstrated that HR was reduced whereas SAN recovery time (SNRT) was prolonged in aged mice; however, both parameters showed heteroscedasticity suggesting differences in health status among mice of similar chronological age. Consistent with this, HR and corrected SNRT were correlated with, and graded by, FI score. Optical mapping of the SAN demonstrated that conduction velocity (CV) was reduced in aged hearts in association with reductions in diastolic depolarization (DD) slope and action potential (AP) duration. In agreement with in vivo results, SAN CV, DD slope and AP durations all correlated with FI score. Finally, SAN dysfunction in aged mice was associated with increased interstitial fibrosis and alterations in expression of matrix metalloproteinases, which also correlated with frailty. These findings demonstrate that age-related SAN dysfunction occurs in association with electrical and structural remodelling and that frailty is a critical determinant of health status of similarly aged animals that correlates with changes in HR and SAN function.

Moghtadaei M ，Jansen HJ ，Mackasey M ，Rafferty SA ，Bogachev O ，Sapp JL ，Howlett SE ，Rose RA ... -  《-》

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha.

Janczewski AM ，Kadokami T ，Lemster B ，Frye CS ，McTiernan CF ，Feldman AM ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY》

A procedure for creating a frailty index based on deficit accumulation in aging mice.

Parks RJ ，Fares E ，Macdonald JK ，Ernst MC ，Sinal CJ ，Rockwood K ，Howlett SE ... -  《-》