Cardiovascular autonomic dysfunction after stroke.

Strokes are the paradigmatic example of the sudden impairment of the cerebral regulation of cardiac autonomic regulation. Although several aspects of dysautonomic cardiovascular regulation post stroke remain unanswered, there has been a wealth of research in this area in the last decade. In this article, we present a state-of-the-art review on the anatomical and functional organization of cardiovascular autonomic regulation, and the pathophysiology, incidence, time course, diagnosis, clinical aspects, prognosis, and management of post-stroke cardiovascular autonomic dysfunction.

Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.

Abnormal motor unit firing rates in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: Patients with CIDP have impairments, including muscle weakness, that could be consequences of demyelination, conduction block, and eventually axonal loss and denervation, leading to muscle atrophy. Consequently, motor unit (MU) activation of the muscle may be impaired contributing to weakness; but this has not been explored in CIDP. METHODS: MU firing rates were recorded at four levels of voluntary isometric dorsiflexion contractions (25%, 50%, 75% and 100% of maximal voluntary contraction [MVC]) in 8 (6 male, 2 female) patients with CIDP and 7 (4 male, 3 female) controls. RESULTS: Patients with CIDP were 33% weaker. The mean MU firing rates of the CIDP group were ~ 19 Hz at 25%, ~16 Hz at 50% MVC, ~18 Hz at 75% MVC and ~ 17 Hz at 100% MVC. The controls had rates of ~13 Hz at 25%, ~18 Hz at 50% MVC, ~32 Hz at 75% MVC and ~ 40 Hz at 100% MVC. Surface root mean squared electromyography normalized to the MVC was less in patients with CIDP at 50 and 75% MVC. CONCLUSIONS: As a consequence secondary to MU loss, patients with CIDP demonstrate significantly lower mean firing rates at high contraction intensities, and higher mean firing rates at low contraction intensities.

Evidence of Impaired Cerebellar Connectivity at Rest and During Autonomic Maneuvers in Patients with Autonomic Failure.

The objective of the current study was to investigate whether patients with neurogenic orthostatic hypotension (NOH) secondary to autonomic failure have impaired functional connectivity between the cerebellum and central autonomic structures during autonomic challenges. Fifteen healthy controls (61 ± 14 years) and 15 NOH patients (67 ± 6 years; p = 0.12) completed the following tasks during a functional brain MRI: (1) 5 min of rest, (2) 5 min of lower-body negative pressure (LBNP) performed at - 35 mmHg, and (3) Three, 15-s Valsalva maneuvers (VM) at 40 mmHg. Functional connectivity (Conn Toolbox V18) between central autonomic structures and discrete cerebellar regions involved in cardiovascular autonomic control, including the vermis and posterior cerebellum, was assessed using a regions-of-interest approach during rest, LBNP and VM. Functional connectivity was contrasted between controls and patients with autonomic failure. At rest, controls had significantly more intra-cerebellar connectivity and more connectivity between cerebellar lobule 9 and key central autonomic structures, including: bilateral anterior insula (TR-value: 4.84; TL-value: 4.51), anterior cingulate cortex (T-value: 3.41) and bilateral thalamus (TR-value: 3.95; TL-value: 4.51). During autonomic maneuvers, controls showed significantly more connectivity between cardiovascular cerebellar regions (lobule 9 and anterior vermis) and important autonomic regulatory sites, including the brainstem, hippocampus and cingulate: vermis-brainstem (T-value: 4.31), lobule 9-brainstem (TR-value, 5.29; TL-value, 4.53), vermis-hippocampus (T-value, 4.63), and vermis-cingulate (T-value, 4.18). Anatomical and functional studies in animals and humans substantiate a significant role for the cerebellum in cardiovascular autonomic control during postural adjustments. In the current study, patients with NOH related to autonomic failure showed evidence of reduced connectivity between cardiovascular cerebellar regions and several important central autonomic structures, including the brainstem. The cerebellum is an established structure in cardiovascular autonomic control; therefore, evidence of impaired cerebellar connectivity to other autonomic structures may further contribute to the inability to properly regulate blood pressure during postural changes in NOH patients.

The Orthostatic Discriminant and Severity Scale (ODSS): an assessment of orthostatic intolerance.

PURPOSE: To assess the ability of the Orthostatic Discriminant and Severity Scale (ODSS) to distinguish symptoms of orthostatic intolerance from non-orthostatic symptoms. METHODS: Clinical evaluations and questionnaire responses were collected in 73 healthy controls and 132 patients referred to the Autonomic Disorders Clinic from September 1, 2016, through April 30, 2018, for queries regarding autonomic dysfunction. A receiver operating characteristic (ROC) curve analysis was used to interpret sensitivity and specificity and to determine cutoff scores for symptom assessment. Inter-item reliability was assessed using Cronbach's alpha. To calculate positive and negative predictive powers, patient data were collected in a single-blinded fashion where the researcher collecting questionnaire data was blinded to the clinical evaluation and diagnosis. Predictive powers were calculated using a chi-squared cross-tabulation. RESULTS: The orthostatic and non-orthostatic symptoms scores produced ROC curves with an area under the curve of 0.89 and 0.79, respectively. The orthostatic scores yielded a positive and negative predictive power value of 73% and 81%, respectively. Combined, the ODSS identified patients with and without orthostatic symptoms with an overall accuracy of 76%. The reliability of the ODSS was significant, with a Cronbach's alpha of 0.88, and all dichotomous items were deemed worthy of retention following an inter-item reliability assessment. CONCLUSIONS: The ODSS demonstrated a strong ability to distinguish patients with and without orthostatic intolerance and demonstrated sensitivity and specificity equivalent to that of other standardized measures. Overall, the ODSS produces symptom scores that are both reliable and useful for both research and clinical practice.

Nerve dysfunction leads to muscle morphological abnormalities in chronic inflammatory demyelinating polyneuropathy assessed by MRI.

Neuropathic features of chronic inflammatory demyelinating polyneuropathy (CIDP) have been well documented, however very little is known about the implication of this neuropathy on skeletal muscle, and whether nerve lesions in CIDP lead to uniform disruptions in skeletal muscles. In this study, we assessed the triceps surae complex, using magnetic resonance imaging (MRI) in a group (n = 10) of CIDP patients compared with a healthy age-matched control group (n = 9). MRI (T1 and T2) of the leg musculature as well as plantar flexion strength measurements were obtained from both groups. CIDP patients compared with controls had ∼28% lower plantar flexion strength and ∼19% less total muscle volume (T1) of the triceps surae. When strength was normalized to fat corrected triceps surae volume CIDP patients were ∼30% weaker than controls. Relaxation times from the T2 scans were significantly longer in CIDP with the soleus, medial head of gastrocnemius and lateral head of gastrocnemius showing ∼37%, ∼38% and ∼26% longer relaxation times, respectively. CIDP patients were significantly weaker compared to controls and despite normalizing strength to total triceps surae contractile tissue volume this difference remained. CIDP patients had significantly longer T2 times, reflecting increased noncontractile tissue infiltration. These results indicate reduced muscle quantity and quality as a result of alterations in axonal function. Furthermore, when present study results are considered together with a prior report on the anterior compartment (Gilmore et al. 2016, Muscle Nerve 3:413-420), it is clear that both anterior and posterior leg compartments are affected similarly in CIDP despite different terminal nerve innervation and functional properties. Clin. Anat. 32:77-84, 2019. © 2019 Wiley Periodicals, Inc.

An Evaluation of Heart Rate Variability in Female Youth Soccer Players Following Soccer Heading: A Pilot Study.

Most head impacts in soccer occur from purposeful heading; however, the link between heading and neurological impairment is unknown. Previous work suggests concussion may result in an uncoupling between the autonomic nervous system and cardiovascular system. Accordingly, heart rate variability (HRV) may be a sensitive measure to provide meaningful information regarding repetitive heading in soccer. The purpose of this pilot study assesses the feasibility of measuring HRV to evaluate autonomic function following soccer heading. Sixteen youth female participants underwent heart rate monitoring during a heading and footing condition. Participants completed a five minute resting supine trial at the start and end of each testing session. Standard 450 g soccer balls were projected at 6 m/s towards participants. Participants performed five headers, for the header condition, and five footers for the footer condition. The HRV for resting supine trials, pre- and post-header and footer conditions were assessed for both time and frequency domains. HRV effect sizes were small when comparing conditions, except absolute low frequency (d = 0.61) and standard deviation of the normal-normal (NN) intervals (d = 0.63). Participant retention and adherence were high, without adverse events. Findings suggest HRV is a feasible measure for evaluating the effects of heading on autonomic function.

Neurogenic orthostatic hypotension impairs information processing speed and attention.

Neurogenic orthostatic hypotension (NOH) is characterized by a drop in systolic blood pressure (SBP) ≥20 mmHg or diastolic blood pressure (DBP) ≥10 mmHg within three minutes of upright posture. NOH is common in the elderly population. This group of individuals is at an increased risk for deficits in multiple cognitive domains such as information processing speed (IPS) and attention. The objective of the current study was to investigate the change in IPS and attention during head-up tilt (HUT) in patients with NOH compared to controls. Cognitive function was assessed in the supine and HUT positions using the symbol digit modalities test (SDMT) which assesses IPS and the Stroop Test which measures attention. 40 participants completed the study, 20 controls (age 64.50 ±â€¯9.25) and 20 NOH patients (age 69.55 ±â€¯7.43) with associated conditions of Parkinson's disease (n = 11), multiple systems atrophy (n = 3), early Lewy body dementia (n = 1) and idiopathic NOH (n = 5). NOH patients had no difference in IPS between supine (43.20 ±â€¯15.26) and HUT (42.90 ±â€¯14.33; p = .77). Controls had significantly faster IPS in the HUT position (69.90 ±â€¯12.02) compared to supine (63.55 ±â€¯9.96; p < .001). NOH patients had significantly slower IPS in both the supine and HUT position compared to controls (p < .001). Attention in the HUT position was significantly worse in NOH patients (-14.86 ±â€¯8.96) compared to controls (-8.68 ±â€¯7.13; p = .029). During HUT, NOH patients experienced a significant decrease in mean SBP by -64.11 ±â€¯18.96 from baseline, whereas controls only had a mean decrease of -5.69 ±â€¯7.65. It is evident that NOH patients have impaired IPS and attention compared to controls and likely plays an important role in the morbidity of these individuals.

Reduced brainstem functional connectivity in patients with peripheral autonomic failure.

Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures. Together, these sites make up, in part, the central autonomic network. Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes. Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure. Fifteen controls (63 ±â€¯13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ±â€¯6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan. Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls. At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (TRIGHT-value: 3.83; TLEFT-value:4.25) (p-FDR < 0.005). During Valsalva, controls showed significantly more connectivity between the brainstem and both the left anterior (cerebellum 4/5) and bilateral posterior cerebellum (cerebellar 9 and left cerebellar 6). Other cerebellar regions included brainstem-to-vermis. Other brainstem-to-cortical and subcortical regions included: bilateral putamen, posterior cingulate cortex (PCC), amygdala and medial prefrontal cortex. There was a significant negative correlation between the brainstem-cerebellar connectivity and severity of autonomic dysfunction (p < .01). During recovery phase of the Valsalva, controls had greater brainstem connectivity to the left thalamus (T-value:4.17); PCC (T-value:3.32); right putamen (T-value:3.28); right paracingulate gyrus (T-value:3.25) and left posterior cerebellum (C9) (T-value:3.21) (p-FDR < 0.05). The effect sizes for each brainstem connectivity during Valsalva and recovery ranged from moderate to strong. Patients with autonomic failure show reduced coupling between the brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices. Connectivity was associated with autonomic impairment. These findings may suggest impaired brainstem connectivity in patients with autonomic failure.

Initial validation of symptom scores derived from the orthostatic discriminant and severity scale.

OBJECTIVE: To develop a scale to quantify and discriminate orthostatic from non-orthostatic symptoms. In the current study, we present validation and reliability of orthostatic and non-orthostatic symptom scores taken from the orthostatic discriminate and severity scale (ODSS). METHODS: Validity and reliability were assessed in participants with and without orthostatic intolerance. Convergent validity was assessed by correlating symptoms scores with previously validated tools [autonomic symptom profile (ASP) and the orthostatic hypotension questionnaire (OHQ)]. Clinical validity was assessed by correlating scores against standardized autonomic testing. Test-retest reliability was calculated using an intra-class correlation coefficient. RESULTS: Convergent validity: orthostatic (OS) and non-orthostatic (NS) symptom scores from 77 controls and 67 patients with orthostatic intolerance were highly correlated with both the orthostatic intolerance index of the ASP (OS: r = 0.903; NS: r = 0.651; p < 0.001) and the composite score of the OHQ: (OS: r = 0.800; NS: r = 0.574; p < 0.001). Clinical validity: symptom scores were significantly correlated with the total composite autonomic severity score (OS: r = 0.458; NS: r = 0.315; p < 0.001), and the systolic blood pressure change during head-up tilt (OS: r = - 0.445; NS: r = - 0.354; p < 0.001). In addition, patients with orthostatic intolerance had significantly higher symptom scores compared to controls (OS: 66.5 ± 18.1 vs. 17.4 ± 12.9; NS: 19.9 ± 11.3 vs. 10.2 ± 6.8; p < 0.001, respectively). Test-retest reliability: Both orthostatic and non-orthostatic symptom scores were highly reliable (OS: r = 0.956 and NS: r = 0.574, respectively; p < 0.001) with an internal consistency of 0.978 and 0.729, respectively. INTERPRETATION: Our initial results demonstrate that the ODSS is capable of producing valid and reliable orthostatic and non-orthostatic symptom scores. Further studies are ongoing to test sensitivity, specificity and symptom severity.

An updated normative data set from the autonomic reflex screen representative of Southwestern Ontario.

In evaluating autonomic dysfunction, the autonomic reflex screen (ARS) is an established set of standardized tests to evaluate the presence and severity of autonomic dysfunction. Our laboratory previously reported normative data on 121 healthy individuals; however, the sample size in older individuals was reduced compared with other age groups. Therefore, the objective of the current study was to provide updated normative values representative of young, middle-aged, and older individuals from Southwestern Ontario. Two hundred and fifty-two healthy individuals completed quantitative sudomotor axon reflex testing, heart rate responses to deep breathing (HRDB), and Valsalva maneuver using standard protocols of the ARS. All 4 sweat sites demonstrated a significant effect of sex (p < 0.001). In addition, the proximal leg, distal leg, and foot were all significantly affected by age (p < 0.001). Cardiovagal parameters, measured via HRDB and Valsalva ratio revealed a significant regression with age (p < 0.001). These results show similar trends with previously reported normative data sets. All normative data as a function of age and sex, where appropriate, are expressed as percentiles (2.5th, 5th, 95th, 97.5th). The current study provides updated normative data describing autonomic functioning in healthy individuals obtained from the sudomotor and cardiovagal components of the ARS.

Cerebellar impairment during an orthostatic challenge in patients with neurogenic orthostatic hypotension.

OBJECTIVE: Compare activation patterns within the cortical autonomic network in patients with neurogenic orthostatic hypotension (NOH) versus healthy age-matched controls during an orthostatic challenge. METHODS: Fifteen health controls and 15 NOH patients performed 3 Valsalva maneuvers, and 5-min of lower-body negative pressure (LBNP) during a functional brain MRI. RESULTS: Compared to controls, NOH patients had significantly less activation within the cerebellum during both LBNP and VM. Both groups had significant activation of the bilateral insula and left thalamus during LBNP. No significant differences were found during the recovery phase of LBNP. CONCLUSIONS: The cerebellum, which plays an important role in vestibulo-sympathetic reflexes, important for blood pressure adjustments during postural changes, appear to be affected in patients with NOH. The cerebellum also appears to be affected during other baroreflex mediated stressors such as the VM. SIGNIFICANCE: Orthostatic reflexes mediated by the cerebellum may be impaired in patients with NOH. The results suggest an additional pathological pathway in patients with autonomic failure.

Impaired cortical autonomic responses during sympathetic activation in neurogenic orthostatic hypotension characterized by postganglionic autonomic dysfunction.

Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Therefore, our objective was to investigate whether impairment of CAN structures is involved in the pathophysiology of NOH. Fifteen controls (63 ± 13 yr) and 15 NOH patients (67 ± 6 yr; P = 0.2) with peripheral autonomic dysfunction completed standard tests of parasympathetic [deep breathing (DB)] and sympathetic [Valsalva maneuver (VM)] activation during a functional MRI. Blood-oxygen-level dependent (BOLD) contrasts were obtained and contrasted. Compared with controls, patients had significantly smaller heart rate responses to DB (control: 15.23 ± 9.6 vs. NOH: 5.7 ± 2.1) and Valsalva ratios (control: 2.1 ± 0.47 vs. NOH: 1.2 ± 0.1; P < 0.001). NOH patients had absent adrenergic phases (late phase II and phase IV) during VM as per a qualitative analysis. During VM, controls had greater activation in the right hippocampus (T-value: 8.03), left posterior cingulate (TL: 7.6), and bilateral thalamus (TR: 7.41, TL: 8.45; P < 0.05). During phase IV, controls had greater activation in the right hippocampus (TR: 5.78l P < 0.05). Following subtraction analysis, no significant differences were evident during DB. In conclusion, NOH patients have significantly less CAN activation during sympathetic, but not parasympathetic, activation. Impaired CANs associated with sympathetic activation may be involved in the pathophysiology of NOH. NEW & NOTEWORTHY Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction characterized by failure of reflexive sympathetic activation. Our result reveal that patients with autonomic dysfunction caused by postganglionic sympathetic impairment also have impaired activation of structures within the cortical autonomic network. Impaired activation is evident during a test of sympathetic, but not parasympathetic, activation. Impaired cortical autonomic networks associated with sympathetic activation may be involved in the pathophysiology of NOH.

Reductions in muscle quality and quantity in chronic inflammatory demyelinating polyneuropathy patients assessed by magnetic resonance imaging.

INTRODUCTION: Weakness in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) may be caused by decreases in muscle quantity and quality, but this has not been explored. METHODS: Twelve patients with CIDP (mean age 61 years) and 10 age-matched (mean age 59 years) control subjects were assessed for ankle dorsiflexion strength, and two different MRI scans (T1 and T2) of leg musculature. RESULTS: Isometric strength was 36% lower in CIDP patients compared with controls. Tibialis anterior muscle volumes of CIDP patients were smaller by ∼17% compared with controls, and non-contractile tissue volume was ∼58% greater in CIDP patients. When normalized to total muscle or corrected contractile volume, strength was ∼29% and ∼18% lower, respectively, in CIDP patients. DISCUSSION: These results provide insight into the structural integrity of muscle contractile proteins and pathologic changes to whole-muscle tissue composition that contribute to impaired muscle function in CIDP. Muscle Nerve 58: 396-401, 2018.

Role of melatonin in blood pressure regulation: An adjunct anti-hypertensive agent.

Cardiovascular diseases account for approximately one-third of all deaths each year. Of this, hypertension accounts for approximately 9.4 million deaths. Melatonin, the primary circadian hormone, has been substantiated as an effective and safe adjunct anti-hypertensive agent. In support of this, melatonin receptors have been identified within the central and peripheral nervous system, as well as the cardiovascular system, including various vascular tissues. Therefore, it is not surprising that recent research has emerged highlighting a key role of melatonin in autonomic regulation of blood pressure. In animals, pinealectomies elicit peripheral vasoconstriction and hypertension. In studies involving humans, both healthy controls and patient populations of essential and nocturnal hypertension, melatonin administration demonstrates significant hypotensive effects that yield clinically significant results. However, the precise mechanism by which melatonin elicits its hypotensive effects in humans require further investigation. This review focuses on melatonin, its role within the cardiovascular system and the emerging implications for its use as an anti-hypertensive agent. Additionally, this review will discuss the current thinking on potential mechanisms behind the hypotensive effects of melatonin including: endothelium-dependent vasodilation, anti-oxidant defence mechanisms and sympatho-vagal autonomic regulation.

Utility of Time and Frequency Domain Parameters of Heart Rate Variability in the Context of Autonomic Disorders Characterized by Orthostatic Dysfunction.

PURPOSE: The clinical significance of heart rate variability in the context of autonomic dysfunction continues to be a matter of debate. A consensus is lacking on the best heart rate variability measures for clinical purposes. Therefore, the purpose of this study was to investigate the utility of heart rate variability parameters in healthy versus autonomic dysfunction. METHODS: Healthy young (n = 134), healthy older (n = 32), and patients with mild (postural tachycardia syndrome; n = 25) and severe (neurogenic orthostatic hypotension; n = 34) autonomic dysfunction were included. Time and frequency parameters during baseline, head-up tilt (HUT), and heart rate response to deep breathing (HRDB) were compared. RESULTS: Cardiovagal time parameters were significantly reduced during HUT in healthy young and postural tachycardia syndrome (P < 0.001). Healthy young had significantly higher time parameters during baseline, HUT, and HRDB (P < 0.01). This was reflected by a significantly lower resting heart rate (HR) (61.4 ± 9.0 bpm vs. 76.8 ± 13.6 bpm; P < 0.001) and a smaller [INCREMENT]HR during HUT (32.8 ± 10.5 bpm vs. 44.4 ± 13.3 bpm; P < 0.001). Time parameters increased in young and postural tachycardia syndrome during HRDB, which was characterized by a nonsignificant difference in [INCREMENT]HR between both groups. Time parameters were significantly higher in healthy old versus neurogenic orthostatic hypotension at rest and during HRDB (P < 0.05). During HUT, only the SD of all normal RR intervals remained significantly higher. Heart rate changes corroborated these findings. Resting HR was significantly lower in healthy older (62.6 ± 11.0 bpm vs. 70.7 ± 12.4 bpm), and [INCREMENT]HR during HRDB was significantly higher (15.9 ± 9.2 bpm vs. 3.9 ± 4.2 bpm; P < 0.001). During HUT, [INCREMENT]HR showed no significant differences. CONCLUSIONS: Time domain parameters of heart rate variability have a greater utility than frequency parameters in clinical autonomic disorders.

Comparison of Heart Rate Variability Parameters to the Autonomic Reflex Screen in Postural Orthostatic Tachycardia Syndrome and Neurogenic Orthostatic Hypotension.

PURPOSE: The clinical significance of heart rate variability (HRV) in the context of autonomic dysfunction continues to be a matter of debate. Therefore, the purpose of the current study was to investigate the clinical relevance of HRV in the context of autonomic dysfunction. METHODS: Heart rate variability data from 225 volunteers consisting of controls (n = 166) and patients with mild (n = 25) and severe (n = 34) autonomic dysfunction were retrospectively analyzed. Time and frequency parameters were correlated against baseline and standardized tests of autonomic function. RESULTS: During baseline, resting HR was negatively correlated with time (SD of all normal RR interval, r = -0.511; RMSSD, r = -0.585; pNN50, r = -0.545) and frequency (low-frequency, r = -0.362; high-frequency, r = -0.421) parameters (P < 0.01). Resting systolic blood pressure demonstrated similar significant correlations (P < 0.01). During head-up tilt, SD of all normal RR intervals was positively correlated with [INCREMENT]HR and change in systolic blood pressure (r = 0.340; r = 0.538, respectively; P < 0.01). Similarly, low-frequency, high-frequency, and low-frequency/high-frequency ratios were correlated with [INCREMENT]HR (r = 0.422, r = 0.176, r = 0.470) and change in systolic blood pressure (r = 0.451, r = 0.407, and r = 0.185) (P < 0.01). Time parameters (SD of all normal RR intervals, RMSSD, and pNN50) were all significantly correlated with deep breathing (r = 0.600; r = 0.556; r = 0.516; P < 0.01, respectively). Low-frequency and high-frequency power were also correlated (r = 0.596; r = 0.580, respectively) (P < 0.01). CONCLUSIONS: Time and frequency parameters showed significant negative correlations with baseline hemodynamics. During a test of sympathetic activation and parasympathetic withdrawal, this relationship shifted to reveal significant positive correlations between HRV parameters and hemodynamics. Last, during a test of parasympathetic activation, there were significant positive correlations with cardiovagally mediated HRV parameters. Overall, these results suggest broader clinical relevance for HRV parameters within the spectrum of autonomic functioning.