Feridooni H A, Kane A E, Ayaz O, Boroumandi A, Polidovitch N, Tsushima R G, Rose R A, Howlett S E
Department of Pharmacology, Dalhousie University, PO Box 15000, 5850 College St, B3H 4R2, Halifax, NS, Canada.
Department of Biology, Muscle Health Research Centre, York University, 4700 Keele St, Toronto, ON, Canada, M3J 1P3.
J Physiol. 2017 Jun 15;595(12):3721-3742. doi: 10.1113/JP274134. Epub 2017 May 14.
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 Ca transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca 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.
心脏大小随年龄增长而增加（称为肥大），其收缩能力下降。然而，这些反映的是平均变化，在所有老年个体中可能并不存在，或者程度不同。临床上普遍认为衰老的速度因人而异。快速衰老的人很虚弱，而虚弱程度是通过“虚弱指数”来衡量的。我们使用经过验证的小鼠虚弱指数工具对虚弱进行量化，并评估年龄和虚弱对心脏肥大和收缩功能障碍的影响。肥大随年龄增长而增加，而收缩、钙电流和钙瞬变则下降；这些变化根据虚弱评分进行分级。整体健康状况（以虚弱来量化）可能会促进与心脏衰老相关的适应性不良变化，并加速诸如心力衰竭等疾病的发展。为了解心脏结构和功能的年龄相关变化，了解动物的实际年龄和健康状况至关重要。
平均而言，心脏肥大和收缩功能障碍随年龄增长而增加。然而，个体衰老的速度不同，其健康状况从健康到虚弱各不相同。我们研究了虚弱对年龄依赖性心室重塑的影响。通过采用经过验证的虚弱指数（FI）工具，将成年（约7个月）和老年（约27个月）C57BL/6J小鼠的虚弱量化为缺陷积累。在Langendorff灌注心脏中评估肥大和收缩功能；在心室肌细胞中研究细胞相关因素/机制。FI评分随年龄增长而增加。平均心脏肥大随年龄增长而增加，但成年组和老年组的值有重叠。当作为虚弱的函数绘制时，肥大根据FI评分进行分级（r = 0.67 - 0.55，P < 0.0003）。心肌细胞面积也与FI呈正相关（r = 0.34，P = 0.03）。左心室舒张末压（LVDP）以及压力上升速率（+dP/dt）和下降速率（-dP/dt）随年龄下降，并且这根据虚弱进行分级（LVDP、+dP/dt和 -dP/dt的r分别为 -0.51，P = 0.0007；r = -0.48, P = 0.002；r = -0.56, P = 0.0002）。在心室肌细胞中也观察到根据FI评分分级的较小、较慢的收缩。从虚弱小鼠分离的心肌细胞中的收缩功能障碍归因于基础钙瞬变的平行变化。这些变化不是由于肌浆网储存减少，而是根据较小的钙电流（r = -0.40，P = 0.008）、较低的增益（r = -0.37，P = 0.02）和Cav1.2蛋白表达降低（r = -0.68，P = 0.003）进行分级。这些结果表明，自然衰老小鼠的心脏肥大和收缩功能障碍根据整体健康状况进行分级，并表明除实际年龄外，虚弱还可以帮助解释心脏衰老的异质性。
