Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in “intrinsic heart rate” (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that age-dependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L- and T-type Ca²⁺ currents and the “funny current” (I_f), and a hyperpolarizing shift in the voltage dependence of I_f. The age-dependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L- and T-type Ca²⁺ currents, and I_f. Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging.One of the most insidious aspects of growing older is an inevitable decline in maximum heart rate (mHR), which limits maximum aerobic capacity with advancing age (1–3). The decline in mHR proceeds at approximately the same rate for all individuals, without regard for lifestyle or physical fitness (4–8). For many otherwise healthy elderly people, it is the factor that ultimately restricts the ability to live independently (9, 10).The decrease in mHR with age results primarily from a parallel age-dependent decline in “intrinsic heart rate” (iHR) (11–13), which is measured during autonomic blockade, and thus reflects the spontaneous pacemaker activity of the sinoatrial node of the heart. Although it is known that the intact sinoatrial node from aged animals contracts more slowly (14, 15) and contains fewer pacemaker myocytes (16), little is known about the functional properties of individual myocytes from the sinoatrial node of the aged heart.Sinoatrial myocytes (SAMs) are highly specialized cells that serve a primarily electrical function as cardiac pacemakers via their production of spontaneous action potentials (APs). Sinoatrial APs are characterized by a spontaneous depolarization during diastole that drives the membrane potential to threshold, thereby triggering the subsequent AP. This “diastolic depolarization” (DD) phase of the sinoatrial AP results from the coordinated activity of numerous membrane conductances, including L- and T-type Ca²⁺ currents (I_Ca,L and I_Ca,T, respectively) and the “funny current” (I_f), all of which contribute directly to the DD by conducting inward current at diastolic potentials (17–23). I_Ca,L also contributes indirectly to the DD by stimulating Ca²⁺ efflux from the sarcoplasmic reticulum of SAMs (24), thereby activating the Na⁺-Ca²⁺ exchange current (I_NCX), which is also known to be critical for normal pacemaker activity (25–29).In this study, we determined the effects of aging on heart rates (HRs) and on spontaneous APs and membrane currents in acutely isolated SAMs. We observed age-dependent decreases in AP firing rates (FRs) in SAMs that corresponded to the age-dependent reductions in iHRs and mHRs. The slower AP FRs resulted from changes in the AP waveform that were associated with an increase in cell size and with alterations in I_Ca,L, I_Ca,T, and I_f. These findings indicate that changes in expression and/or regulation of ion channels in SAMs comprise part of the molecular program that limits mHR, and thus aerobic capacity, during normal aging.