The Pathogenesis and Treatment of Cardiovascular Autonomic Dysfunction in Parkinson's Disease: What We Know and Where to Go

Abstract

Cardiovascular autonomic dysfunctions (CAD) are prevalent in Parkinson's disease (PD). It contributes to the development of cognitive dysfunction, falls and even mortality. Significant progress has been achieved in the last decade. However, the underlying mechanisms and effective treatments for CAD have not been established yet. This review aims to help clinicians to better understand the pathogenesis and therapeutic strategies. The literatures about CAD in patients with PD were reviewed. References for this review were identified by searches of PubMed between 1972 and March 2021, with the search term "cardiovascular autonomic dysfunctions, postural hypotension, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension, and nondipping". The pathogenesis, including the neurogenic and non-neurogenic mechanisms, and the current pharmaceutical and non-pharmaceutical treatment for CAD, were analyzed. CAD mainly includes four aspects, which are OH, SH, postprandial hypotension and nondipping, among them, OH is the main component. Both non-neurogenic and neurogenic mechanisms are involved in CAD. Failure of the baroreflex circulate, which includes the lesions at the afferent, efferent or central components, is an important pathogenesis of CAD. Both non-pharmacological and pharmacological treatment alleviate CAD-related symptoms by acting on the baroreflex reflex circulate. However, pharmacological strategy has the limitation of failing to enhance baroreflex sensitivity and life quality. Novel OH treatment drugs, such as pyridostigmine and atomoxetine, can effectively improve OH-related symptoms via enhancing residual sympathetic tone, without adverse reactions of supine hypertension. Baroreflex impairment is a crucial pathological mechanism associated with CAD in PD. Currently, non-pharmacological strategy was the preferred option for its advantage of enhancing baroreflex sensitivity. Pharmacological treatment is a second-line option. Therefore, to find drugs that can enhance baroreflex sensitivity, especially via acting on its central components, is urgently needed in the scientific research and clinical practice.

Keywords: Parkinson’s disease; cardiovascular autonomic dysfunction; orthostatic hypotension; postprandial hypotension; supine hypertension.

Figure 1.

Triple whammy possible mechanisms of OH in PD. This figure describes the three mechanisms of neurogenic orthostatic hypotension. NOH in PD seems to reflect a “triple whammy” of cardiac and extra-cardiac noradrenergic denervation. Decreased BP stimulates arterial baroreceptors including carotid sinus, aortic arch and great vessels leading to a compensatory baroreflex response. Baroreceptor impulses are transmitted to the nucleus of the tractus solitarius (NTS) in the dorsomedial medulla along the afferent fibers, — the glossopharyngeal and vagus nerves. This is an inhibitory afferent fiber, that reduces impulse transmission to the NTS, which transmits signals to the nucleus ambiguous (NA), and the vagus nerve input from the nucleus ambiguous is reduced. At the same time, the NTS transmits signals to the rostral ventrolateral medulla connecting with the intermediolateral cell column of the thoracic spinal cord, and the sympathetic efferent nerve activity increases from the intermediolateral cell column of the thoracic spinal cord. Norepinephrine is the dominant neurotransmitter in the sympathetic efferent limb. Norepinephrine is the main neurotransmitter of sympathetic efferent limbs. The rapid increase of norepinephrine in response to standing, and an important pathophysiological mechanism of orthostatic hypotension in PD patients is its impaired response. NOH manifests with failure of baroreflex systems with or without sympathetic noradrenergic denervation. As a response to the continuous decrease of BP, the release of vasopressin is mediated by the projection of the A1 noradrenergic cell population in the ventrolateral medulla. The vasopressin-producing neurons in the magnocellular portion of the paraventricular nucleus and the supraoptic nucleus of the hypothalamus will be activated by this projection, resulting in increased HR, cardiac output and vasoconstriction. Cardiac and extra-cardiac noradrenergic denervation, baroreflex failure,and the decrease of noradrenaline release are also associated with ageing. Cardiac noradrenergic denervation can decrease heart rate and cardiac output. Extra-cardiac sympathetic denervation leads to a decrease in the release of norepinephrine, resulting in decreased peripheral vasoconstriction, reduced return heart blood volume, and eventual decreased BP.