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    • br Discussion With recently improved understanding of

    2022-11-17


    Discussion With recently improved understanding of the role of βARK1 in the progression of HF and as a potential therapeutic target in HF, we explored the relationship between plasma βARK1, as a marker of chronic sympathetic overactivation, and physical symptoms in HF. Our main findings were 1) elevated plasma βARK1 was significantly associated with worse physical symptoms after adjusting for other clinical characteristics, and 2) plasma βARK1 provides more information in differentiating physical symptoms in HF compared with the SHFM. The observed relationship provides preliminary evidence of the role of sympathetic overactivation, as measured by plasma βARK1, in explaining the biological underpinnings of physical symptoms in HF. βARK1 has been shown to improve (i.e. decrease) among patients implanted with a ventricular assist device and following cardiac transplantation, suggesting that a decrease in βARK1 would track with improved symptoms. As chronic sympathetic overactivation is a hallmark of HF pathophysiology, it seems logical that decreased sympathetic activity would result in better symptoms perhaps through better exercise capacity or ability to respond acutely to catecholamines; however, more research using a longitudinal design and multimarker approach is needed to fully understand this relationship. Specifically, it will be important to understand autonomic balance by integrating additional sympathetic and parasympathetic markers and how these change in relation to symptoms and exercise capacity, particularly when followed by interventions. A clinical implication from this study is that sympathetic overactivation is one pathophysiologic mechanism that underlies physical symptom burden in HF. Given the little-to-no association between what we measure objectively (e.g. hemodynamics) and what patients experience symptomatically,4, 5, 6 this is an important next step in identifying a biological underpinning of physical symptoms in HF. These findings, coupled with other advances in HF symptom biology,19, 20 could inform conversations in clinical settings, especially when eliciting information regarding symptom burden. Moreover, these results could provide an amenable target for ameliorating symptom burden through interventions directed at reducing sympathetic overdrive, including a combination of pharmacological, exercise, and self-care interventions.7, 21, 22
    Conclusions
    Introduction Noradrenaline and adrenaline are some of the most important all trans retinoic acid in the nervous system. However, the effects of noradrenergic/adrenergic modulation on the striatum have not been explored due to a lack of evidence of direct noradrenergic/adrenergic neuron projections into the striatum (Baldo et al., 2003, Berridge and Waterhouse, 2003, Berridge et al., 1997, Jones and Yang, 1985, Swanson and Hartman, 1975). Nonetheless, the presence of noradrenaline in the striatum is firmly established. Striatal noradrenaline levels in freely moving rodents immediately increase responding to unconditioned stimuli (handling and novelty) (Cenci et al., 1992, Ihalainen et al., 1999) and repetitive locus coeruleus (LC) electrical stimulations (Devoto et al., 2005). Abundant adrenergic receptor (AR) expression is confirmed in the striatum. While β-ARs are primarily found on striatal postsynaptic membranes and cell bodies (Hara et al., 2010, Nicholas et al., 1996, Paschalis et al., 2009, Pisani et al., 2003), α1-ARs are found on pre-synaptic terminals in the striatum (Rommelfanger et al., 2009). On the cellular level, although there exists a report of AR-dependent DARPP-32 phosphorylation in the striatum (Hara et al., 2010), there are no reports of how AR ligands modulate striatal electrical properties. In order to inquire into how noradrenaline and adrenaline modulate the striatal functions, we measured the adrenergic modulation on the striatal firing pattern. A good example of the importance of adrenergic modulation can be seen in Parkinson's disease (PD). Noradrenergic and adrenergic changes have come to be regarded as important factors of PD symptoms (Delaville et al., 2011, LeWitt, 2012, Ostock and Bishop, 2014). Although the primary known cause of PD symptoms is the striatal dopamine level reduction induced by the loss of dopaminergic neurons in the substantia nigra (SN), there is a considerable loss of noradrenergic neurons in LC as well (Braak et al., 2003, Halliday et al., 2006, Zarow et al., 2003). Moreover, the pathological changes of LC neurons and melanized projecting neurons in the medulla oblongata precede the SN lesions (Braak et al., 2003). In addition, the noradrenaline loss produces more profound motor deficits than dopaminergic deprivation (Pifl et al., 2013, Rommelfanger et al., 2007). Clinically, it is well-known that β-agonists aggravate tremors in PD patients (Constas, 1962) and β-antagonists alleviate the tremors (Crosby et al., 2003, Foster et al., 1984). β-Antagonists are also effective for reducing dyskinesia in PD patients (Carpentier et al., 1996). Knowing noradrenergic/adrenergic modulation on striatal activity is crucial in understanding PD pathology and the drug treatment mechanisms (Delaville et al., 2011, LeWitt, 2012, Ostock and Bishop, 2014).