Rhythm dynamics of the aging heart: an experimental study using conscious, restrained mice

Abstract

Heart rate variability (HRV) is a measure of variation in time interval between heartbeats and reflects the influence of autonomic nervous system and circulating/locally released factors on sinoatrial node discharge. Here, we tested whether electrocardiograms (ECGs) obtained in conscious, restrained mice, a condition that affects sympathovagal balance, reveal alterations of heart rhythm dynamics with aging. Moreover, based on emergence of sodium channels as modulators of pacemaker activity, we addressed consequences of altered sodium channels on heart rhythm. C57Bl/6 mice and mice with enhanced late sodium current due to Nav1.5 mutation at Ser571 (S571E), at ~4 to ~24 months of age were studied. HRV was assessed using time- and frequency-domain and nonlinear parameters. For C57Bl/6 and S571E mice, standard deviation of RR intervals (SDRR), total power of RR interval variation, and nonlinear standard deviation 2 (SD2) were maximal at ~4 months and decreased at ~18 and ~24 months, together with attenuation of indices of sympathovagal balance. Modulation of sympathetic and/or parasympathetic divisions revealed attenuation of autonomic tone at ~24 months. At ~4 months, S571E mice presented lower heart rate and higher SDRR, total power, and SD2 with respect to C57Bl/6, properties reversed by late sodium current inhibition. At ~24 months, heart rate decreased in C57Bl/6 but increased in S571E, a condition preserved after autonomic blockade. Collectively, our data indicate that aging is associated with reduced HRV. Moreover, sodium channel function conditions heart rate and its age-related adaptations, but does not interfere with HRV decline occurring with age.

Slowing down as we age: aging of the cardiac pacemaker’s neural control

“…A reduction in the parasympathetic tone occurs with age and it has been suggested to compensate for the pacemaker intrinsic slowdown [61,62]. Heart rate variability, which is largely accepted to reflect the parasympathetic modulation of the heart, decreases by more than 60% from 20-year-old to 60-year-old subjects [63][64][65], suggesting a loss of parasympathetic tone with age. Interestingly, a biological model has been proposed to explain the decrease in heart rate variability.…”

“…A reduced responsivity to the parasympathetic drive can also be attributable to a common mechanism such as a reduction of cAMP/PKA sensitivity [ 99 ] or an age-reduced sensitivity to phosphodiesterase inhibition [ 96 ]. Parasympathetic input then appears to be attenuated in old animals, generating an abnormal sympathovagal balance with age [ 65 ].…”

Transcriptome-wide N6-methyladenine methylation in granulosa cells of women with decreased ovarian reserve

“…Data showed that a bunch of genes displayed different m 6 A methylation levels and differently expressed mRNA levels (Table 4 ). Most of these hyper- or hypo- methylated and differently expressed genes were reported to have a role in aging of human and other mammalian species, such as NAV1, FOXO6, CARD6, FAHD1, TCF4, DNMBP, and HMGCS 1 [ 46 – 52 ]. Some of the genes were confirmed to be enrolled in the process of ovarian tumorgenesis, such as FBXO16, TTYH3, VSIG4, ZC3H13, NCK1, BMI1, USP1, DYRK2, DNAJB6, TNC, KLF12, LATS2, and FOXP1 [ 53 – 65 ].…”

Heart Rate Variability Reveals Altered Autonomic Regulation in Response to Myocardial Infarction in Experimental Animals

“…plus propranolol (1 mg/kg body weight, i.p.) for combined block of sympathetic and parasympathetic branches of the autonomic nervous system (combined autonomic block) ( 24 , 28 ). Drugs were dissolved in USP saline solution.…”

“…Analysis of heart rate and heart rate variability (HRV) was conducted on electrocardiographic recordings using LabChart 8 (ADinstruments) and the HRV module, as reported previously ( 24 ). Lead I was used to obtain HRV parameters and other leads were employed as alternative source of analysis and/or for validation of obtained results.…”