Temporal Development of Autonomic Dysfunction in Heart Failure: Effects of Age in an Ovine Rapid-pacing Model

Abstract

Heart failure (HF) is predominantly a disease of older adults and characterized by extensive sympatho-vagal imbalance leading to impaired reflex control of heart rate (HR). However, whether aging influences the development or extent of the autonomic imbalance in HF remains unclear. To address this, we used an ovine model of aging with tachypacing-induced HF to determine whether aging affects the chronotropic and inotropic responses to autonomic stimulation and reduction in heart rate variability (HRV) in HF. We find that aging is associated with increased cardiac dimensions and reduced contractility before the onset of tachypacing, and these differences persist in HF. Additionally, the chronotropic response to β-adrenergic stimulation was markedly attenuated in HF, and this occurred more rapidly in aged animals. By measuring HR during sequential autonomic blockade, our data are consistent with a reduced parasympathetic control of resting HR in aging, with young HF animals having an attenuated sympathetic influence on HR. Time-domain analyses of HR show a reduction in HRV in both young and aged failing animals, although HRV is lowest in aged HF. In conclusion, aging is associated with altered autonomic control and β-adrenergic responsiveness of HR, and these are exacerbated with the development of HF.

PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure

“…We next sought to determine if the increase in symptom-free survival following tadalafil treatment was associated with any changes in cardiac contractility or cardiac dimensions. In line with our previous findings 1, [33][34][35] left ventricular dilatation and free wall thinning were observed following tachypacing ( Figure 1B & C). Tadalafil treatment did not reverse left ventricular dilatation but did normalize diastolic wall thickness from its nadir value observed one week after commencement of tadalafil treatment.…”

Increased Ca buffering underpins remodelling of Ca2+ handling in old sheep atrial myocytes

“…Decreased heart rate variability in old sheep (Horn et al . ) suggests that an age‐associated increase in sympathetic tone is preserved across species. Sympathetic tone, activating β‐adrenoceptors, probably exacerbates the age‐associated increase in SR Ca content (Briston et al .…”

“…In a separate group of animals, we have previously shown that, although the heart rate increases with age, spontaneous AF or left ventricular hypertrophy do not occur (Horn et al . , )…”

“…Animals demonstrating minor ailments such as non-malignant dermatological and ocular conditions were included in the study, and these pathologies might be expected to occur more frequently in older animals (Rockwood et al 2017). In a separate group of animals, we have previously shown that, although the heart rate increases with age, spontaneous AF or left ventricular hypertrophy do not occur (Horn et al 2012(Horn et al , 2016…”

“…Sympathetic nerve activity increases with age in man accompanied by a decrease in heart rate variability (Abhishekh et al 2013). Decreased heart rate variability in old sheep (Horn et al 2016) suggests that an age-associated increase in sympathetic J Physiol 595.19 tone is preserved across species. Sympathetic tone, activating β-adrenoceptors, probably exacerbates the age-associated increase in SR Ca content (Briston et al 2011) without affecting Ca buffering (Briston et al 2014) and may therefore increase the probability of spontaneous SR Ca release (Venetucci et al 2007).…”