The prevalence of heart failure is 70 times higher in persons aged 65 or older than in those aged 20–34.
Approximately 80% of hospital admissions for heart failure in the US involve patients aged > 65 years.
Cardiac functional reserve declines with age and cardiac aging is a continuous and irreversible process that accounts for the most common cause of death in elderly people The aging heart displays left ventricular wall thickening and myocardial enlargement.
Although interactions among advanced age, occult disease and physical inactivity have been considered in interpreting age-associated changes in cardiovascular function, the ‘aging process’ itself has been proved to be independently related to change of cardiac structure and performance such as cardiac hypertrophy and prolonged myocardial contraction.
Several cellular mechanisms are thought to be involved in cardiac aging, including prolonged action potential duration, altered myosin heavy chain (MHC) isoform expression and sarcoplasmic reticulum (SR) function, all of which may lead to changes in cardiac excitation–contraction (E-C) coupling.
Cardiac E-C coupling cycle or cardiac cycle has been demonstrated to be prolonged with increased age, probably due to cytosolic Ca2+ overload-induced dysregulation of cytosolic Ca2+.
The cytosolic Ca2+ load is determined by multiple factors, including membrane structure and permeability, the regulatory proteins within the membrane, and reactive oxygen species (ROS), which affect both membrane structure and function.
However, the link between advanced age and altered cardiac E-C coupling has not been fully understood.
Therefore, the aim of the study was to examine the effect of aging on cardiomyocyte contractile function and its causal relationship with cardiac protein oxidation, accumulation of advanced glycation endproducts (AGEs) and protein oxidative modification.
The mechanical properties were evaluated in ventricular myocytes from young (2-month) and aged (24–26-month) mice using a MyoCam® system.
The mechanical indices evaluated were peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (± dL/dt).
Oxidative stress and protein damage were evaluated by glutathione and glutathione disulfide (GSH/GSSG) ratio and protein carbonyl content, respectively.
Activation of NAD(P)H oxidase was determined by immunoblotting.
Aged myocytes displayed a larger cell cross-sectional area, prolonged TR90, and normal PS, ± dL/dt and TPS compared with young myocytes.
Aged myocytes were less tolerant of high stimulus frequency (from 0.1 to 5 Hz) compared with young myocytes.
Oxidative stress and protein oxidative damage were both elevated in the aging group associated with significantly enhanced p47 phox but not gp91 phox expression.
In addition, level of cardiac AGEs was ~2.5-fold higher in aged hearts than young ones determined by AGEs-ELISA.
A group of proteins with a molecular range between 50 and 75 kDa with pI of 4–7 was distinctively modified in aged heart using one- or two-dimension SDS gel electrophoresis analysis.
These data demonstrate cardiac diastolic dysfunction and reduced stress tolerance in aged cardiac myocytes, which may be associated with enhanced cardiac oxidative damage, level of AGEs and protein modification by AGEs.
Oxidative stress and protein oxidative damage in cardiac tissue.
A representative gel depicting the patterns of total cardiac protein oxidation from both young and aged groups by immunostaining using anti-dinitrophenylhydrazine (DNPH) Western blot.
Mean ± SEM, n = 8.
*P < 0.05 vs. young group.
Representative gels depicting cardiac protein non-enzymatic glycation immunostaining using anti-AGE monoclonal antibody (6D12).
(A) One-dimensional SDS gel electrophoresis analysis showed the cardiac proteins modified by AGEs.
Two-dimensional SDS gel electrophoresis analysis demonstrated the proteins modified by AGEs from the young group (B) and old group (C).