Low-Frequency Oscillations in Cardiac Sympathetic Neuronal Activity

Abstract

Sudden cardiac death caused by ventricular arrhythmias is among the leading causes of mortality, with approximately half of all deaths attributed to heart disease worldwide. Periodic repolarization dynamics (PRD) is a novel marker of repolarization instability and strong predictor of death in patients post-myocardial infarction that is believed to occur in association with low-frequency oscillations in sympathetic nerve activity. However, this hypothesis is based on associations of PRD with indices of sympathetic activity that are not directly linked to cardiac function, such as muscle vasoconstrictor activity and the variability of cardiovascular autospectra. In this review article, we critically evaluate existing scientific evidence obtained primarily in experimental animal models, with the aim of identifying the neuronal networks responsible for the generation of low-frequency sympathetic rhythms along the neurocardiac axis. We discuss the functional significance of rhythmic sympathetic activity on neurotransmission efficacy and explore its role in the pathogenesis of ventricular repolarization instability. Most importantly, we discuss important gaps in our knowledge that require further investigation in order to confirm the hypothesis that low frequency cardiac sympathetic oscillations play a causative role in the generation of PRD.

ECG Ventricular Repolarization Dynamics during Exercise: Temporal Profile, Relation to Heart Rate Variability and Effects of Age and Physical Health

“…In silico studies have suggested that synergistic β-adrenergic stimulation and mechanical stretch could contribute to explain the LF oscillatory pattern of ventricular repolarization [ 40 , 41 ]. Although further research is needed to mechanistically link LF oscillations in ventricular repolarization to LF rhythmic discharge of sympathetic neurons [ 9 ], our study, together with all cited evidences from cell to whole-body levels, provide indirect support to the involvement of the sympathetic nervous system in the generation of the observed oscillatory behavior.…”

“…This, together with other more mechanistic investigations, could help elucidate the grounds underlying the predictive capacity of elevated PRD. Those grounds could involve not only a higher vulnerability of the myocardium to arrhythmogenic LF repolarization oscillations but a higher release of norepinephrine and arrhythmogenic co-transmitters due to larger neuronal synchronization, as proposed in [ 9 ]. Additionally, further research should confirm whether PRD and its RRV-unrelated component, both measured at rest and in response to exercise, could be useful to assess chronic effects of age, BMI and cardiorespiratory fitness level on ventricular activity and its relationship to cardiac risk, in general, and arrhythmic risk, in particular.…”

“…Sympathetic nervous system (SNS) hyperactivity has been shown to increase triggered activity and enhance dispersion of ventricular repolarization under different clinical conditions, thus contributing to accentuate the vulnerability to fatal ventricular arrhythmias and sudden cardiac death [ 9 ]. Recent studies have proposed an electrocardiogram (ECG)-based risk predictor, which has been suggested to reflect sympathetic effects on ventricular myocardium [ 10 ].…”

“…The physiological mechanisms underlying the genesis of PRD are yet to be fully described, particularly regarding the direct involvement of sympathetic oscillatory activity on regulation of the ventricular myocardium [ 9 ]. The importance of LF oscillations in providing information potentially related to sympathetic neural activity has been described through different markers obtained from the T-wave vector, sympathetic nerve activity recordings, HRV, action potentials or systolic arterial blood pressure [ 9 ].…”

“…The physiological mechanisms underlying the genesis of PRD are yet to be fully described, particularly regarding the direct involvement of sympathetic oscillatory activity on regulation of the ventricular myocardium [ 9 ]. The importance of LF oscillations in providing information potentially related to sympathetic neural activity has been described through different markers obtained from the T-wave vector, sympathetic nerve activity recordings, HRV, action potentials or systolic arterial blood pressure [ 9 ]. Specifically regarding PRD, clinical and experimental studies have so far provided evidence that it is enhanced by sympathetic activation, induced by either tilt table test or exercise, and suppressed by pharmacological β-adrenergic blockade [ 10 , 16 ].…”