Neurodegenerative synucleinopathies, including Parkinson disease (PD) and other neurodegenerative diseases causing central or peripheral neuropathies, may be characterized by autonomic dysfunction, which severely affects both cardiovascular and noncardiovascular systems under sympathetic and parasympathetic control.1 As the integral role of the autonomic nervous system (ANS) is to regulate bodily functions, its dysfunction and degeneration are implicated in the development of comorbid disease states, which can further impair patient quality of life and shorten overall survival.1–4 Therefore, autonomic dysfunction can have substantial implications relevant to cardiovascular management practices.
Manifestations of autonomic dysfunction in PD and related conditions are common and widespread, reflecting the extensive role of the ANS across bodily systems. These manifestations include dysphagia, constipation, urinary urgency, incontinence, erectile dysfunction, orthostatic and postprandial hypotension, dyshidrosis, and impaired thermoregulation.1 Of the cardiovascular disorders associated with synucleinopathies, neurogenic orthostatic hypotension (nOH) is the hallmark manifestation of ANS dysfunction.1,5 In contrast to non-nOH, which can be caused by medications (eg, diuretics and vasodilators), impaired venous return (venous pooling), hypovolemia, or impaired cardiac output, nOH is a form of OH that results as a consequence of neurodegenerative disease of either the peripheral or central nervous system.6
Another common cardiovascular disorder that often occurs as a result of autonomic failure in synucleinopathies is supine hypertension (SH).7 The clinical management of nOH and SH may be counterintuitive and challenging (especially when they occur in combination) because of opposing hemodynamics and/or treatment incompatibility. Here, we review ANS regulation of the cardiovascular system with a focus on the sympathetic and parasympathetic nervous systems (SNS and PNS), as well as the pathophysiology, clinical manifestations, diagnosis, and management approaches for these manifestations of cardiovascular autonomic dysfunction, from both cardiology and neurology perspective.
THE AUTONOMIC NERVOUS SYSTEM
The ANS regulates bodily functions to maintain homeostasis and coordinates the acute response to threat or danger. It comprises the SNS, PNS, and enteric nervous systems (ENS).8 The SNS and PNS are anatomically and functionally distinct and use different sets of neurotransmitter systems; their activation largely results in antagonistic effects.8 The ENS, consisting of the myenteric and submucosal plexi, is involved in the control and coordination of the gastrointestinal (GI) tract, including motility, blood flow, and secretions.9,10 Although it is considered an independent system,9 the ENS may be inhibited by signals from the sympathetic component of the ANS, in accordance with relative bodily needs.11
The SNS prepares the body for the fight or flight response, and the PNS is involved in rest and digest responses.12 Upon activation, the SNS induces responses including increased heart rate (HR) and force of ventricular contraction (positive chronotropism and positive inotropism, respectively), decreased GI tract motility, pupil dilation, bronchodilation, decreased reproductive system function, slightly increased glandular secretion, and mobilization of energy substrates.8 The primary neurotransmitter of the SNS is norepinephrine.13 Upon activation of the PNS, responses include decreased HR and cardiac force of contractility (negative chronotropism and negative inotropism, respectively), enhanced GI tract motility, pupil constriction, bronchoconstriction, and substantial secretion from lacrimal and salivary glands.8 The main postganglionic neurotransmitter of the PNS is acetylcholine.14
AUTONOMIC NERVOUS SYSTEM’S REGULATION OF THE CARDIOVASCULAR SYSTEM
The intrinsic conduction system of the heart produces an impulse originating from the rhythmic discharge of the sinoatrial node, which determines the HR.15 The ANS regulates HR and cardiac output depending on physiologic conditions, ensuring that the heart performs optimally both at rest and when an acute response is needed.15,16
The anatomy of the ANS associated with regulation of the heart is depicted in Figure 1.16 Sympathetic cardiac nerve fibers stem from the upper thoracic region of the spinal cord; these are short preganglionic efferent nerve fibers that enter the paravertebral chains of ganglia and synapse with longer postganglionic sympathetic efferents that extend to the sinoatrial and atrioventricular nodes in the heart.16 Upon activation, the preganglionic efferents release acetylcholine that binds to nicotinic receptors on the postganglionic efferents; in turn, the postganglionic efferents, which are adrenergic, release norepinephrine at synapses that have β-adrenergic receptors.16 The results are increases in HR, force of ventricular contraction, rate of relaxation, and conduction velocity of the sinoatrial and atrioventricular nodes, all of which are fundamental for the fight or flight response.16
Parasympathetic control of the heart is mediated by long preganglionic efferent nerve fibers that stem from the vagus nerve and synapse near the sinoatrial and atrioventricular nodes.16 Activation of the parasympathetic nerve fibers releases acetylcholine, which, in turn, activates muscarinic receptors in the sinoatrial and atrioventricular nodes.16 The results are decreases in HR, force of ventricular contraction, rate of relaxation, and conduction velocity of the sinoatrial and atrioventricular nodes, which are all characteristic of the rest and digest response.16,17
The SNS has a primary role in autonomic regulation of the vasculature, innervating arteries, veins, and microvessels.18 Activation of sympathetic nerve fibers triggers the release of 3 main neurotransmitters—norepinephrine, adenosine triphosphate (ATP), and neuropeptide Y—all of which have a role in mediating vasoconstriction.18 Norepinephrine and ATP are released together to produce rapid adrenergic and purinergic vasoconstriction as a result of vascular smooth muscle cell contraction. Neuropeptide Y is released along with norepinephrine and ATP in response to moderate to intense sympathetic activation, producing slow and sustained vasoconstriction. Neuropeptide Y may also potentiate vasoconstriction in response to norepinephrine.18
The ANS is also responsible for signaling the cardiovascular system for the necessary acute response to orthostatic stresses created by moving from a supine to a sitting or standing position. The role of the ANS in maintaining cardiovascular homeostasis during changes in posture is presented in Figure 2.19 Change from a supine or seated to a standing position triggers blood pressure (BP) regulatory mechanisms that increase HR, cardiac contractility, and vascular tone to maintain sufficient perfusion of vital organs.20 When moving to a standing position, blood shifts from the thorax to the lower body (venous pooling), and BP drops as a result.6 Baroreceptors in the cardiovascular and pulmonary vessels detect the decrease in BP and respond by withdrawing parasympathetic activity and increasing sympathetic activity, thereby increasing BP.6,20
PATHOPHYSIOLOGY OF AUTONOMIC NERVOUS SYSTEM FAILURE IN NEURODEGENERATIVE DISEASES
Formation and accumulation of misfolded protein aggregates of α-synuclein is the pathognomonic feature of the synucleinopathies PD, Lewy body dementia (LBD), pure autonomic failure, and multiple system atrophy (MSA).21 α-Synuclein has been recognized as the main component of the Lewy body in both PD and LBD, suggesting that aggregation of α-synuclein may play a dominant role in the neurodegenerative processes seen in these diseases.22 Further evidence has confirmed that abnormal aggregation of α-synuclein plays a central role in PD and related disorders; however, its normal function and mechanism of involvement in neurodegeneration are not completely understood.23
In PD, LBD, and pure autonomic failure, α-synuclein forms intraneural aggregates as Lewy bodies and neuronal neurites,24,25 leading to both central and peripheral neurodegeneration and denervation (in PD).26 In MSA, α-synuclein aggregation occurs mainly in oligodendritic structures termed glial cellular inclusions, resulting in only central nervous system lesions.26 Progressive neurodegeneration of the ANS in patients with MSA may be clinically manifested as nOH, erectile dysfunction in men, urinary incontinence, and constipation.6
In addition to α-synuclein aggregation, significantly lower levels of norepinephrine have been found in postmortem studies of PD in several brain regions, including the caudate, middle frontal gyrus, anterior cingulate gyrus, hippocampus, amygdala, inferior parietal lobule, precuneus, and visual association cortex.27 Low norepinephrine levels are associated with OH as demonstrated in a study that found significantly lower plasma levels of norepinephrine in patients who had PD with OH but not in patients who had PD without OH.28 Furthermore, cardiac noradrenergic denervation has been demonstrated in the thoracic region by positron emission tomography studies in patients with pure autonomic failure, PD, and MSA, although normal innervation is seen in most patients with MSA (Figure 3).29,30 Preserved innervation in MSA reflects a centrally mediated pathophysiology,26 whereas in pure autonomic failure and PD, it reflects a postganglionic sympathetic lesion.1 The resulting impairment of cardiovascular homeostasis in PD manifests as increased difficulty in making HR adjustments to changes in BP and in the development of nOH, baroreflex dysfunction, and nighttime fluid retention.31 In MSA, cardiovascular dysregulation resulting in nOH is a prevalent characteristic.32 [123I]-Metaiodobenzylguanidine scintigraphy can also be used to assess cardiac sympathetic innervation to distinguish between conditions of peripheral (PD and pure autonomic failure) versus central (MSA) autonomic failure.33 Decreased baroreflex-cardiovagal gain occurs with normal aging and has also been observed in patients with PD and patients with OH.34,35 Baroreflex-cardiovagal gain is normally measured through determination of the cardiac interbeat interval (RR interval) response in relation to systolic BP changes after intravenous injection of a vasoconstrictor or vasodilator.35 Together with sympathetic failure resulting in a sustained drop in BP when standing, HR increases to compensate for low BP and consequently decreases the cardiac interbeat interval. Decreased baroreflex-cardiovagal gain manifests as dizziness and may lead to blackout.35,36
COMMON CONDITIONS THAT MAY RESULT FROM AUTONOMIC DYSFUNCTION
Neurogenic Orthostatic Hypotension
In healthy individuals, venous return of blood to the heart is increased by muscle contraction to prevent pooling in lower parts of the body.37 ANS responses to changes in position include vasoconstriction and increased HR and cardiac contractility.6 However, in individuals with nOH, autonomic dysfunction results in hemodynamic abnormalities that are clinically manifested as a drop in BP upon standing.37 nOH is a form of OH defined as a sustained reduction of systolic BP of ≥ 20 mm Hg or diastolic BP of ≥ 10 mm Hg within 3 minutes of standing or using a head-up tilt table for autonomic testing.37,38 nOH occurs when the ANS does not respond adequately to counteract the gravitational shift in blood volume; thus, there is a sustained fall in BP that is associated with an insufficient increase in HR (typically < 15 bpm).39,40
nOH is considered to be a manifestation of norepinephrine deficiency,41 as described previously for synucleinopathies. The prevalence of nOH is reported at 30% to 40% in PD,1 50% in LBD,42,43 >75% in MSA,44 and 97% in pure autonomic failure.45
Several studies have suggested an impact of OH/nOH on the risk of falls and injuries, societal costs, and psychosocial effects (eg, fear of falling and deterioration of quality of life).46–49 OH/nOH is a known risk factor for falls. Not only does a clear relationship exist between OH/nOH and falling in older adults (30% and 45% incidence in patients aged 65–75 and > 80 years, respectively),46,47 but recurrent falls associated with nOH in PD are common and affect approximately 70% of patients with PD.48 Although falls may lead to injury, it has been demonstrated that the fear of falling rather than actual falls contributes to poorer health-related quality of life in patients with PD.49 A Scottish study of adults > 65 years of age found the annual estimated cost of falls and fall-related injuries to be £471 million (approximately $630 million USD); this included both direct healthcare costs and indirect social/residential care costs.46
The diagnosis of nOH is based on clinical manifestations including dizziness/lightheadedness, presyncope, syncope, weakness, and falls.36 Screening questions are used to identify suspected OH/nOH, and a stepwise approach is recommended for diagnosis. Steps include in-clinic monitoring of BP and HR after 5 minutes in a supine position, which is repeated after 1 and 3 minutes of standing, and at-home BP and HR monitoring after 5 minutes in a supine position or before arising in the morning, which is repeated after 3 minutes of standing, and again while standing when symptomatic. A sit-to-stand test, with at least 5 minutes of sitting and then monitoring of BP immediately before standing and 1, 3, 5, and 10 minutes (as tolerated) after standing, may be a suitable alternative to monitoring BP upon standing after spending 5 minutes in a supine position.36,50 A review of medications should be performed to assess the necessity for reduction or modification of medications that may cause OH. The patient’s medical history, including cardiovascular comorbidities, review of systems, and current medication list, should be assessed, and a reasonable physical examination and 12-lead electrocardiogram should be performed to delineate potential causes of OH/nOH. Finally, specialty testing may be considered; possible tests include autonomic testing, plasma catecholamines, sudomotor function testing, and 24-hour ambulatory BP monitoring to help distinguish OH from nOH.36
The main goals for treatment per nOH consensus recommendations include reduction of symptom burden (especially falls), prolongation of standing time, and improvement of physical capabilities to enable the patient to perform activities of daily living. The consensus recommendations advise initial interventions, which entail implementation of a 4-step algorithm, with patient reassessment every 2 weeks to discern the benefits of such interventions. Assessment and adjustment of current medications should be performed first, followed by the use of nonpharmacologic approaches. If nOH persists, implementation of single-agent pharmacologic treatment should be considered, and finally combination pharmacologic treatments can be applied with careful assessment of symptomatic benefits, impact on BP, and tolerability.36
Pharmacologic options for the management of nOH currently include both approved and off-label medications. The 2 agents currently approved by the US Food and Drug Administration for the treatment of OH and nOH are midodrine, an α-1 adrenergic agonist, and droxidopa, a prodrug of norepinephrine, respectively. Both drugs increase BP by improving vasoconstriction6,36; although a slowing of HR is associated with midodrine administration,51 droxidopa has limited effects on HR.52 Systematic reviews and meta-analyses evaluating the short-term (1 day to 4 weeks) effects of midodrine on BP and symptoms of OH found that midodrine treatment may result in small but positive effects on clinical outcomes in patients with OH.53,54 However, the evidence for midodrine was considered low quality because of the small number of studies and heterogeneity among the studies analyzed.53,54 Three short-term (1–8 weeks of treatment), randomized, placebo-controlled, double-blind phase 3 studies with droxidopa in patients with symptomatic nOH due to synucleinopathy (PD, MSA, and pure autonomic failure) demonstrated improvement in specific symptoms of nOH (eg, dizziness/lightheadedness).55–58 Drugs frequently used off label for the treatment of OH/nOH36 include fludrocortisone, a glucocorticoid that acts to expand plasma volume,59 and pyridostigmine, a cholinesterase inhibitor that enhances sympathetic activity by increasing baroreflex sensitivity.60 The use of β-blockers may worsen the symptoms of nOH because the resultant decreased sympathetic activity, in turn, generates a negative impact on the inotropic/chronotropic state. It is noteworthy that pacemakers are not recommended for the treatment of nOH.36,61
Coexistent Neurogenic Orthostatic Hypotension and Supine Hypertension
SH coexistent with nOH is associated with negative clinical sequelae, including cardiovascular outcomes,62 and is part of the underlying disease process in patients with autonomic failure.36 SH in patients with nOH is defined as systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg while in the supine position for ≥ 5 minutes.63 SH frequency has been reported for PD (34%; 71% mild), MSA (37%; 28% severe), and MSA with OH (49%; 44% severe).62 In PD, SH is associated with a history of cardiovascular comorbidities and more pronounced drops in BP with orthostatic challenge.62 SH has been associated with target end-organ damage (eg, left ventricular hypertrophy64 and kidney dysfunction65) and negative cardiovascular outcomes, such as the occurrence of stroke.66
SH has been shown to coexist with nOH in 50% to 90% of patients with PD.67 Dilemmas in management arise with concurrent disease because SH and nOH represent opposite hemodynamics, and as such, when these conditions are coexistent, specific treatments for nOH or SH may exacerbate the other condition. For example, pressor medications used to treat nOH may exacerbate SH, whereas short-acting antihypertensives used to treat SH may worsen symptoms of nOH.7,36 A change in mean BP over a period of 24 hours can include abnormally low BP during the day due to orthostatic stress and abnormally high BP at night due to prolonged recumbence (Figure 4).31 Impairment of the sympathetic network activation underlies the development of nOH; together with other consequences of sympathetic failure (eg, baroreflex dysfunction, adrenergic hypersensitivity, and nocturnal fluid retention), parasympathetic dysfunction may also contribute to aggravation or development of nocturnal SH. In patients with autonomic failure, a nocturnal dipping pattern (circadian-related ≥ 10% decrease in mean BP at night) is absent—referred to as nondipping or reverse dipping—and results in nocturnal SH.31 Because untreated long-term SH has known cardiac consequences, it is reasonable to seek treatment options; however, coexistent SH and nOH should be managed with care. A substantial benefit of prioritizing nOH versus SH treatment exists31 because of a reduction in the risk of falls and the associated complications.36 Patients with nOH and severe SH can, however, be treated with short-acting antihypertensive agents in the evening, with awareness of the risks of worsening nOH.36
Clinical studies directly comparing the risk of SH for droxidopa and midodrine have not been performed. However, a meta-analysis using clinical trial data determined the relative risk for SH with droxidopa (4 studies including 485 patients) was not statistically significant [1.4 (95% CI, 0.71–2.7) vs placebo].68 In contrast, midodrine (2 studies including 349 patients) was associated with a significant relative risk for SH [5.1 (95% CI, 1.6–24.0) vs placebo].68
DISTINGUISHING BETWEEN OTHER POSSIBLE CARDIOVASCULAR MANIFESTATIONS OF AUTONOMIC NERVOUS SYSTEM DYSFUNCTION
Other cardiovascular conditions that may arise because of ANS dysfunction include (but are not limited to) vasovagal syncope, postural orthostatic tachycardia syndrome (POTS), and inappropriate sinus tachycardia (IST). A summary of these conditions is provided in Table 1.37,38,40,69–72
Vasovagal syncope, the most common type of reflex syncope, occurs from a vasovagal reflex that causes vasodilation and/or bradycardia resulting in a rapid and transient loss of consciousness as a consequence of cerebral hypoperfusion, which is followed by complete recovery.69–71 Orthostatic stress (upright position for > 30 seconds), pain, or emotional stress are associated with vasovagal syncope.69,71 Prodromal symptoms in the minute before losing consciousness include pallor, diaphoresis, nausea, abdominal discomfort, yawning, sighing, and hyperventilation. These symptoms are then followed by visual, auditory, and cognitive difficulties.37 Physiologic mechanisms that contribute to vasovagal syncope include decreased cardiac output and reduced systemic vascular resistance.73
Postural Orthostatic Tachycardia Syndrome
POTS, a sustained sinus tachycardia upon standing [HR of ≥ 30 bpm in the absence of OH (or ≥ 40 bpm in individuals 12–19 years of age) within 10 minutes of standing or head-up tilt], without notable change in BP, is typically accompanied by symptoms, such as lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue.37,69 The standing HR for individuals with POTS is often ≥ 120 bpm.69 Loss of consciousness is not a major feature, although presyncope is frequent.37,69,74 The exact causes of POTS remain unknown, and it is likely that multiple factors contribute to the development of this syndrome including autonomic denervation, recent viral illness, chronic fatigue syndrome, hypovolemia, hyperadrenergic stimulation, and hypervigilance.37,69 Importantly, because the symptoms of POTS overlap considerably with vasovagal syncope, the diagnoses of these 2 conditions are often not mutually exclusive.69
Inappropriate Sinus Tachycardia
IST is defined as a persistent resting sinus HR of > 100 bpm (mean 24-hour HR > 90 bpm not related to primary causes).69 The causes of IST have not been elucidated; however, dysautonomia, neurohormonal imbalance, and intrinsic sinus node hyperactivity may play a role.72 Weakness, fatigue, lightheadedness, exercise intolerance, and palpitations help to distinguish IST from secondary causes of tachycardia. Often in patients with IST, medication therapy is unsuccessful and these symptoms persist even after treatment to normalize HR.72,75,76
IMPLICATIONS FOR CARDIOLOGY PRACTICE
High rates of general medical comorbidities are observed in up to 80% of patients with PD. The most common comorbidities in patients with PD are diabetes mellitus, dyslipidemia, arterial hypertension, and cardiomyopathy.67 Although noncardiovascular comorbidities are not the focus of this review, it should be noted that they can further contribute to the burden of cardiovascular disorders. Both cardiovascular and noncardiovascular disorders can develop as adverse effects to PD treatment or as a consequence of autonomic dysfunction, which is characteristic of PD pathology.
ANS disorders of the digestive system can adversely affect GI tract motility and cause hypersalivation, delayed gastric emptying, and constipation. ANS disorders of the cardiovascular system include nOH, which is the most common autonomic disorder in PD; SH, which occurs in addition to nOH in a majority of patients with PD, especially at night; and attenuated HR variability associated with cardiovascular morbidity and mortality.67 Any of these disorders can occur concomitantly, and management of conjunctive disease can be complicated by opposite hemodynamics and/or treatment incompatibility. Because nOH is the most common autonomic manifestation in PD, the implications of OH/nOH in clinical practice are detailed further.
Population-based epidemiologic studies have indicated that OH is associated with increased cardiovascular mortality, myocardial infarction, stroke, heart failure, and atrial fibrillation.2 The increased morbidity and mortality associated with OH has been demonstrated in several studies including patients with and without PD. In a Belgian study of elderly patients, OH was shown to be a significant predictor of cardiovascular deaths, nonfatal myocardial infarctions, and stroke.77 In middle-aged patients who participated in the American Atherosclerosis Risk in Communities Study (ARIC, 1987–2008), the presence of OH at baseline was associated with the increased risk of heart failure and stroke.78,79 Cross-sectional studies, summarized in the Fedorowski and Melander 20132 article, showed pure autonomic failure (with or without PD) or OH to be associated with reverse or nondipping of nocturnal BP,77,80 arterial stiffness,81 left ventricular hypertrophy,82,83 peripheral arterial disease,82 attenuated HR variability,84 increased carotid intima-media thickness, and plasma fibrinogen concentration.85
In studies that investigated nOH in patients with PD and related conditions, comorbidity resulted in shorter overall survival.3 In a prospective cohort study of middle-aged and elderly patients, survival differed depending on the type of synucleinopathy (PD, MSA, and pure autonomic failure); mean survival from symptom onset ranged from 7 years in patients with MSA to 16 years in patients with PD without nOH.3 The presence of nOH in patients with PD was associated with a significantly higher mortality risk versus patients with PD without nOH.3 A retrospective study of middle-aged and elderly patients with nOH and synucleinopathy (MSA, PD with autonomic neuropathy, and pure autonomic failure) evaluated comorbidities and causes of death.4 Observed comorbidities included hypertension, benign prostatic hypertrophy, cerebrovascular accidents, cancer, and gastroenterologic-, psychiatric-, respiratory-, and cardiac-related (including heart failure and atrial fibrillation) comorbidities. Causes of death were infectious/respiratory, cardiac, cachexia, stroke, cancer, and trauma.4 From the findings of these studies, it is clear that nOH often presents with or results in a myriad of comorbidities and complications, all of which adversely affect patient quality of life, morbidity, and mortality.
PD and other synucleinopathies are characterized by autonomic dysfunction, which also severely affects the cardiovascular and noncardiovascular systems under sympathetic and parasympathetic control. Although nOH is the most common ANS dysfunction-mediated cardiovascular manifestation in patients with PD, its coexistence with SH is a clinical challenge. Furthermore, attenuated HR variability, sinus node dysfunction, and chronotropic incompetence can also occur in conjunction with OH. Management of conjunctive disease can be complicated by opposite hemodynamics and/or treatment incompatibility. Additionally, the presence of other noncardiovascular comorbidities may further contribute to the burden of cardiovascular disease and synucleinopathy. Multiple comorbidities effectively impair quality of life and shorten survival in patients with synucleinopathy; this presents major healthcare implications in synucleinopathy and cardiovascular management practices, necessitating an integrative therapeutic approach.
Medical writing assistance was provided by the CHC Group (North Wales, PA) and was supported by Lundbeck.
1. Kaufmann H, Goldstein DS. Autonomic dysfunction in Parkinson disease. Handb Clin Neurol. 2013;117:259–278.
2. Fedorowski A, Melander O. Syndromes of orthostatic intolerance: a hidden danger. J Intern Med. 2013;273:322–335.
3. Goldstein DS, Holmes C, Sharabi Y, et al. Survival in synucleinopathies: a prospective cohort study. Neurology. 2015;85:1554–1561.
4. Maule S, Milazzo V, Maule MM, et al. Mortality and prognosis in patients with neurogenic orthostatic hypotension. Funct Neurol. 2012;27:101–106.
5. Metzler M, Duerr S, Granata R, et al. Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol. 2013;260:2212–2219.
6. Jones PK, Shaw BH, Raj SR. Orthostatic hypotension: managing a difficult problem. Expert Rev Cardiovasc Ther. 2015;13:1263–1276.
7. Jordan J, Fanciulli A, Tank J, et al. Management of supine hypertension
in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension. J Hypertens. 2019;37:1541–1546.
8. Hamill RW, Shapiro RE, Vizzard MA. Robertson D, Biaggioni I, Burnstock G. Peripheral autonomic nervous system. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 17–26.
9. Grundy D, Schemann M. Enteric nervous system. Curr Opin Gastroenterol. 2005;21:176–182.
10. Schemann M, Neunlist M. The human enteric nervous system. Neurogastroenterol Motil. 2004;16(Suppl 1):55–59.
11. Furness JB. The enteric nervous system: normal functions and enteric neuropathies. Neurogastroenterol Motil. 2008;20(Suppl 1):32–38.
12. VanPatten S, Al-Abed Y. The challenges of modulating the ‘rest and digest’ system: acetylcholine receptors as drug targets. Drug Discov Today. 2017;22:97–104.
13. Goldstein DS. Robertson D, Biaggioni I, Burnstock G. Noradrenergic neurotransmission. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 37–43.
14. English BA, Jones CK. Robertson D, Biaggioni I, Burnstock G. Cholinergic neurotransmission. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 71–74.
15. Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol. 2015;7:204–214.
16. Drew RC, Sinoway LI. Robertson D, Biaggioni I, Burnstock G. Autonomic control of the heart. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 177–180.
17. Lewis ME, Al-Khalidi AH, Bonser RS, et al. Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart. J Physiol. 2001;534(Pt. 2):547–552.
18. Lombard JH, Cowley AW Jr. Robertson D, Biaggioni I, Burnstock G. Neural control of blood vessels. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 187–191.
19. Low PA, Tomalia VA, Park KJ. Autonomic function tests: some clinical applications. J Clin Neurol. 2013;9:1–8.
20. Wieling W, Groothuis JT. Robertson D, Biaggioni I, Burnstock G. Physiology of upright posture. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 193–195.
21. Benskey MJ, Perez RG, Manfredsson FP. The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson’s disease. J Neurochem. 2016;137:331–359.
22. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840.
23. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79:1044–1066.
24. Coon EA, Low PA. Pure autonomic failure without alpha-synuclein pathology: an evolving understanding of a heterogeneous disease. Clin Auton Res. 2017;27:67–68.
25. Ubhi K, Crews L, Masliah E. Robertson D, Biaggioni I, Burnstock G. Alpha-synuclein and neurodegeneration. In: Primer on the Autonomic Nervous System. 2012:3rd ed. London, UK: Academic Press; 303–305.
26. Iodice V, Low DA, Vichayanrat E, et al. Cardiovascular autonomic dysfunction in MSA and Parkinson’s disease: similarities and differences. J Neurol Sci. 2011;310:133–138.
27. Buddhala C, Loftin SK, Kuley BM, et al. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. Ann Clin Transl Neurol. 2015;2:949–959.
28. Senard JM, Valet P, Durrieu G, et al. Adrenergic supersensitivity in parkinsonians with orthostatic hypotension. Eur J Clin Invest. 1990;20:613–619.
29. Goldstein DS, Holmes C, Cannon RO 3rd, et al. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med. 1997;336:696–702.
30. Raffel DM, Koeppe RA, Little R, et al. PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes. J Nucl Med. 2006;47:1769–1777.
31. Espay AJ, LeWitt PA, Hauser RA, et al. Neurogenic orthostatic hypotension and supine hypertension
in Parkinson’s disease and related synucleinopathies: prioritisation of treatment targets. Lancet Neurol. 2016;15:954–966.
32. Wenning GK, Colosimo C, Geser F, et al. Multiple system atrophy. Lancet Neurol. 2004;3:93–103.
33. McDonell KE, Shibao CA, Claassen DO. Clinical relevance of orthostatic hypotension in neurodegenerative disease. Curr Neurol Neurosci Rep. 2015;15:78.
34. Goldstein DS, Pechnik S, Holmes C, et al. Association between supine hypertension
and orthostatic hypotension in autonomic failure. Hypertension. 2003;42:136–142.
35. Goldstein DS. Dysautonomia in Parkinson disease. Compr Physiol. 2014;4:805–826.
36. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension
. J Neurol. 2017;264:1567–1582.
37. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69–72.
38. Freeman R, Abuzinadah AR, Gibbons C, et al. Orthostatic hypotension: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72:1294–1309.
39. Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003;68:2393–2398.
40. Shibao C, Lipsitz LA, Biaggioni I. ASH position paper: evaluation and treatment of orthostatic hypotension. J Clin Hypertens (Greenwich). 2013;15:147–153.
41. Loavenbruck A, Sandroni P. Neurogenic orthostatic hypotension: roles of norepinephrine deficiency in its causes, its treatment, and future research directions. Curr Med Res Opin. 2015;31:2095–2104.
42. Thaisetthawatkul P, Boeve BF, Benarroch EE, et al. Autonomic dysfunction in dementia with Lewy bodies. Neurology. 2004;62:1804–1809.
43. Stubendorff K, Aarsland D, Minthon L, et al. The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson’s disease with dementia. PLoS One. 2012;7:e45451.
44. Low PA, Reich SG, Jankovic J, et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 2015;14:710–719.
45. Kaufmann H, Norcliffe-Kaufmann L, Palma JA, et al.; Autonomic Disorders Consortium. Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol. 2017;81:287–297.
46. Craig J, Murray A, Mitchell S, et al. The high cost to health and social care of managing falls in older adults living in the community in Scotland. Scott Med J. 2013;58:198–203.
47. Shaw BH, Claydon VE. The relationship between orthostatic hypotension and falling in older adults. Clin Auton Res. 2014;24:3–13.
48. Allen NE, Schwarzel AK, Canning CG. Recurrent falls in Parkinson’s disease: a systematic review. Parkinsons Dis. 2013;2013:906274.
49. Grimbergen YA, Schrag A, Mazibrada G, et al. Impact of falls and fear of falling on health-related quality of life in patients with Parkinson’s disease. J Parkinsons Dis. 2013;3:409–413.
50. Shaw BH, Garland EM, Black BK, et al. Optimal diagnostic thresholds for diagnosis of orthostatic hypotension with a ‘sit-to-stand test’. J Hypertens. 2017;35:1019–1025.
51. McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs. 1989;38:757–777.
52. Biaggioni I, Arthur Hewitt L, Rowse GJ, et al. Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension. BMC Neurol. 2017;17:90.
53. Izcovich A, González Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review. Neurology. 2014;83:1170–1177.
54. Parsaik AK, Singh B, Altayar O, et al. Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials. J Gen Intern Med. 2013;28:1496–1503.
55. Kaufmann H, Freeman R, Biaggioni I, et al.; NOH301 Investigators. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014;83:328–335.
56. Biaggioni I, Freeman R, Mathias CJ, et al.; Droxidopa 302 Investigators. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65:101–107.
57. Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson’s disease (NOH306A). J Parkinsons Dis. 2014;4:57–65.
58. Hauser RA, Isaacson S, Lisk JP, et al. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson’s disease (nOH306B). Mov Disord. 2015;30:646–654.
59. Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA. 1997;277:1046–1051.
60. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol. 2006;63:513–518.
61. Lahrmann H, Cortelli P, Hilz M, et al. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol. 2006;13:930–936.
62. Fanciulli A, Göbel G, Ndayisaba JP, et al. Supine hypertension
in Parkinson’s disease and multiple system atrophy. Clin Auton Res. 2016;26:97–105.
63. Fanciulli A, Jordan J, Biaggioni I, et al. Consensus statement on the definition of neurogenic supine hypertension
in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). Clin Auton Res. 2018;28:355–362.
64. Vagaonescu TD, Saadia D, Tuhrim S, et al. Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet. 2000;355:725–726.
65. Garland EM, Gamboa A, Okamoto L, et al. Renal impairment of pure autonomic failure. Hypertension. 2009;54:1057–1061.
66. Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension
in autonomic failure patients with orthostatic hypotension. J Clin Hypertens (Greenwich). 2002;4:139–145.
67. Csoti I, Jost WH, Reichmann H. Parkinson’s disease between internal medicine and neurology. J Neural Transm (Vienna). 2016;123:3–17.
68. Chen JJ, Han Y, Tang J, et al. Standing and supine blood pressure outcomes associated with droxidopa and midodrine in patients with neurogenic orthostatic hypotension: a Bayesian meta-analysis and mixed treatment comparison of randomized trials. Ann Pharmacother. 2018;52:1182–1194.
69. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12:e41–e63.
70. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2017;70:e39–e110.
71. Brignole M, Moya A, de Lange FJ, et al.; ESC Scientific Document Group. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39:1883–1948.
72. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the management of adult patients with supraventricular tachycardia: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2016;67:e27–e115.
73. Stewart JM, Medow MS, Sutton R, et al. Mechanisms of vasovagal syncope in the young: reduced systemic vascular resistance versus reduced cardiac output. J Am Heart Assoc. 2017;6:e004417.
74. Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome - diagnosis, physiology, and prognosis. Auton Neurosci. 2018;215:3–11.
75. Olshansky B, Sullivan RM. Inappropriate sinus tachycardia. Europace. 2019;21:194–207.
76. Marrouche NF, Beheiry S, Tomassoni G, et al. Three-dimensional nonfluoroscopic mapping and ablation of inappropriate sinus tachycardia. Procedural strategies and long-term outcome. J Am Coll Cardiol. 2002;39:1046–1054.
77. Fagard RH, De Cort P. Orthostatic hypotension is a more robust predictor of cardiovascular events than nighttime reverse dipping in elderly. Hypertension. 2010;56:56–61.
78. Jones CD, Loehr L, Franceschini N, et al. Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study. Hypertension. 2012;59:913–918.
79. Eigenbrodt ML, Rose KM, Couper DJ, et al. Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study, 1987-1996. Stroke. 2000;31:2307–2313.
80. Okamoto LE, Gamboa A, Shibao C, et al. Nocturnal blood pressure dipping in the hypertension of autonomic failure. Hypertension. 2009;53:363–369.
81. Mattace-Raso FU, van der Cammen TJ, Knetsch AM, et al. Arterial stiffness as the candidate underlying mechanism for postural blood pressure changes and orthostatic hypotension in older adults: the Rotterdam Study. J Hypertens. 2006;24:339–344.
82. Fan XH, Wang Y, Sun K, et al. Disorders of orthostatic blood pressure response are associated with cardiovascular disease and target organ damage in hypertensive patients. Am J Hypertens. 2010;23:829–837.
83. Maule S, Milan A, Grosso T, et al. Left ventricular hypertrophy in patients with autonomic failure. Am J Hypertens. 2006;19:1049–1054.
84. Sato Y, Ichihashi K, Kikuchi Y, et al. Autonomic function in adolescents with orthostatic dysregulation measured by heart rate variability. Hypertens Res. 2007;30:601–605.
85. Fedorowski A, Ostling G, Persson M, et al. Orthostatic blood pressure response, carotid intima-media thickness, and plasma fibrinogen in older nondiabetic adults. J Hypertens. 2012;30:522–529.