Clinical and Neurohormonal Characteristics of African Americans with Neurogenic Orthostatic Hypotension

Abstract

Purpose:

Neurogenic orthostatic hypotension (nOH) is the hallmark of neurodegenerative forms of autonomic failure, such as pure autonomic failure, multiple system atrophy and Parkinson’s disease. Studies have shown autonomic physiological differences in Africans Americans (AA) such as lower heart rate variability, enhanced blood pressure reactivity and blunted sympathetic neural response compared to non-Hispanic whites. However, the clinical characteristics and neurohormonal profile of autonomic failure in AA is unknown.

Methods:

A total of 65 patients with nOH participated in this study (9 AA and 56 non-Hispanic whites). Both groups were of similar age and comorbidity status, and they underwent standardized autonomic testing and assessment of neurohormonal levels and renin activity and aldosterone in supine and upright positions.

Results:

There were no significant differences in baseline autonomic clinical characteristics between non-Hispanic whites and AA with nOH. Non-Hispanic whites demonstrated a significant increase in upright renin activity compared to AA (295 ± 88% vs. 13 ± 13%, respectively). AA showed a blunted increase in aldosterone compared to non-Hispanic whites (188 ± 27% vs. 59 ± 38%, respectively). These results indicated persistent suppression of the renin-angiotensin system in AA, particularly during upright posture.

Conclusion:

Our findings demonstrate that AA with nOH have similar clinical characteristics and hemodynamic autonomic profiles, but lower upright renin activity and aldosterone levels compared to non-Hispanic whites. Renin suppression persist in AA with severe autonomic failure and can potentially contribute to postural changes and supine hypertension.

Introduction

Neurogenic orthostatic hypotension (nOH) is caused by impairment of cardiovascular autonomic reflexes that maintain blood pressure. It is defined as a sustained drop in either systolic blood pressure by ≥20 mmHg or diastolic blood pressure by ≥10 mmHg within three minutes of standing or 60° head-up tilt [1–3]. nOH is a prominent feature of alpha-synucleinopathies, a subset of neurodegenerative autonomic disorders characterized by accumulation of alpha-synuclein aggregates in neurons or glial cells. Alpha-synucleinopathies include Pure Autonomic Failure (PAF), Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), and Parkinson’s disease (PD). PAF is a type of peripheral autonomic failure, wherein alpha-synuclein lesions localize to postganglionic autonomic neurons, resulting in sympathetic and parasympathetic denervation [4]. In contrast, MSA, is a type of central autonomic failure, wherein alpha-synuclein lesions localize to oligodendroglia cytoplasm, resulting in severe autonomic impairment and motor symptoms. Aside from these primary causes of nOH, secondary causes of nOH include aging, diabetes mellitus, amyloidosis, paraneoplastic syndromes, familial dysautonomia and autoimmune-mediated etiologies [1].

The defective release of norepinephrine from sympathetic post-ganglionic neurons is the main pathophysiological cause of nOH. Impaired neurotransmitter release hinders activation of adrenoreceptors, dropping blood pressure, and manifesting as light-headedness, dizziness, and syncope [1, 2]. In addition to these hypotensive episodes, over 50% of patients with nOH also suffer from concomitant supine hypertension (HTN) [1] as well as dysregulation of the autonomic nervous system control of the gastrointestinal and genitourinary functions. Of all these debilitating symptoms of autonomic dysregulation, nOH is a distinctive sign that is often amenable to treatment [5].

As mentioned, aging is a secondary cause and contributor to autonomic instability [3]. Interestingly, physiologic autonomic changes that occur with aging vary between racial groups. Heart rate variability reactivity, a marker of cardioprotective parasympathetic function, declines more rapidly among aging African Americans (AA) compared to non-Hispanic whites [6]. Elderly AA also have enhanced blood pressure reactivity during orthostatic stress, leading to higher blood pressures compared to elderly whites [7]. It has been postulated that the increased blood pressure reactivity in AA may be mediated by excessive sympathetic stimulation through either augmented sympathetic vascular transduction (elevated norepinephrine signal transduction) or nonadrenergic mechanisms that raise blood pressure (upregulated renin-angiotensin-aldosterone signaling or venoarteriolar response) [7]. Of note, the study that demonstrated greater blood pressure response to orthostatic challenge in elderly AA also found a blunted sympathetic neural responsiveness (decreased upright total MSNA) during orthostasis [7]. These findings suggest the presence of differences in autonomic regulation between AA and non-Hispanic whites.

Although there have been some studies on autonomic differences in AA patients, there is a paucity of data describing nOH in AA populations. Given the racial differences observed in autonomic regulation in patients without autonomic failure, it stands to reason that nOH may also have unique features in different racial groups. The purpose of this study was to evaluate the blood pressure response to orthostatic stress and neurohormonal regulatory patterns in AA patients with nOH, and to compare this data to that of non-Hispanic white subjects with nOH referred to a tertiary treatment center for autonomic disorders. The characterization of nOH in AA and the identification of pathophysiological differences between AA and non-Hispanic white subjects with nOH is critical for providing an accurate diagnosis, formulating an appropriate treatment strategy, and determining prognosis for patients. It is especially important to optimize care for a historically understudied and underrepresented population in clinical research.

Methods

Subjects

Patients with nOH due to severe autonomic failure (PAF, MSA, and Parkinson’s disease) were prospectively recruited from the Autonomic Dysfunction Center at Vanderbilt Medical Center between January 2009 and March 2016 as previously described [8]. Patients with autonomic failure secondary to diabetes mellitus, amyloidosis, or paraneoplastic syndrome were excluded from the study. All patients self-identified race as either AA or non-Hispanic whites. Normative data for healthy subjects was obtained from a previous study at Vanderbilt Medical Center assessing sympathetic tone and insulin sensitivity in patients with autonomic failure [9]. These healthy control subjects were recruited from the local community, were nonsmokers, and were excluded if pregnant, had evidence of systemic illness, or were taking medications known to interfere with blood pressure or volume [9]. The study was conducted in accordance with the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects. The study was approved by the Vanderbilt Institutional Review Board and conducted in accordance with institutional guidelines. All subjects provided informed written consent. The study was registered at ClinicalTrials.gov under “Treatment of Orthostatic Hypotension in Autonomic Failure” (NCT00223691).

Procedures

Patients were admitted to the Vanderbilt Clinical Research Center. For at least three days prior to baseline evaluation, subjects consumed a low-monoamine, caffeine-free diet with 150 mEq daily sodium and 60–80 mEq daily potassium. For at least five half-lives prior to admission, all medications affecting the autonomic nervous system, blood pressure, and blood volume were discontinued to allow adequate wash out period.

Standardized Autonomic Testing

All participants underwent an initial screening phase, which consisted of a comprehensive medical history, physical examination, 12-lead ECG, laboratory assessments, autonomic function tests, and orthostatic tests [10]. Autonomic testing included sinus arrhythmia, Valsalva maneuver, hyperventilation, the cold pressor test, and isometric handgrip exercise [11]. All tests were previously standardized in our laboratory [10]. Orthostatic testing was performed to determine hemodynamic and hormonal changes on standing. An indwelling catheter was placed in an antecubital vein to obtain blood samples while patients remained supine after an overnight rest. Orthostatic vital signs were recorded at 1, 3, 5, and 10 minutes or as tolerated by study subjects. Brachial blood pressure and heart rate were measured using an automated brachial sphygmomanometer (Dinamap, GE Medical Systems Information Technologies, Milwaukee, WI) medium size cuff, placed on the right arm. All the procedures followed were performed by trained research nurses and were followed in accordance with standardized approved protocols and institutional guidelines.

Neurohormonal Assessment

Blood samples were collected to measure plasma catecholamines (norepinephrine), renin activity, and aldosterone levels after 30 minutes in the supine and upright positions. High-performance liquid chromatography with electrochemical detection provided plasma catecholamine levels [12]. The conversion of angiotensinogen to angiotensin I was used to assess plasma renin enzymatic activity. Radioimmunoassay measured plasma aldosterone levels [13].

Statistical Analysis

Data are reported as mean ± SEM unless otherwise stated. Figures report mean values with error bars indicating standard error of the mean. Standard graphing and screening techniques were used to detect outliers and ensure data accuracy. We assessed continuous outcomes for normality. If normality was violated, we either applied data transformation or performed non-parametric analysis methods. Summary statistics for both numerical and categorical variables by study groups were provided. We estimated between-group difference in means with standard deviation for the primary endpoints. These differences were tested using either two-sample t-test or Chi-Square test. GraphPad Prism version 8.4.3 was used for data plotting and analysis. We tested all hypothesis at the level of α=0.05.

Results

Baseline Clinical Characteristics

A total of 65 patients with autonomic failure and nOH participated in this trial (N=56 non-Hispanic whites and N=9 AA) and were compared to normative data from 8 healthy control subjects. The clinical characteristics of these patients and controls are presented in Table 1. Approximately 14% of the cohort was comprised of AA, and 86% was non-Hispanic whites. The ages of autonomic failure patients ranged from 49 to 80 years, but were not significantly different between non-Hispanic whites and AA (p = 0.340). The mean age of healthy controls was slightly younger than the study subjects at 62 years. Twenty-five patients (38%) were female in the study group and five (63%) were female in the healthy controls. Height, weight, and BMI were similar between non-Hispanic whites and AA subjects. Patients with autonomic failure were subdivided and analyzed according to primary cause of autonomic failure (PAF, PD, MSA). Baseline clinical characteristics between non-Hispanic whites and AA populations were similar except for a higher percentage of AA with nOH were diagnosed with PD (PD was present in 0 non-Hispanic whites subject vs. 1 AA subject, p = 0.0119). Neurogenic supine hypertension was diagnosed based on the consensus criteria [ie., systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg after five minutes of rest in the supine position] and did not vary significantly between racial groups at baseline [14].

Table 1.

Baseline Clinical Characteristics

Clinical Variable	NH-W	AA	P-value	Healthy
Age (years)	66 ± 2	69 ± 2	0.340	62 ± 3
Male sex (%)	35 (63%)	5 (55%)	0.691	3 (37%)
Height (cm)	173 ± 2	175 ± 4	0.618	166 ± 4
Weight (kg)	81 ± 3	79 ± 5	0.765	75 ± 6
BMI (kg/m2)	26.7 ± 0.6	25.8 ± 0.8	0.567	26.7 ± 1.2
PAF (%)	30 (54%)	6 (67%)	0.463
PD (%)	0 (0%)	1 (11%)	0.0119*
MSA (%)	26 (46%)	2 (22%)	0.174
Disease duration years	5 ± 1	6 ± 2	0.964
Supine Hypertension (%)	38 (68%)	6 (67%)	0.944

Data are reported as mean ± SEM. Healthy values are form control patients in Autonomic Dysfunction Center Database at Vanderbilt University Medical Center. P-values were calculated using Mann-Whitney test or Chi-Square test.

^*P = < 0.05. [NH-W N=56 and AA N=9].

NH-W, non-Hispanic whites, PAF Primary Autonomic Failure, PD Parkinson’s disease, MSA Multiple System Atrophy.

Autonomic Function Tests, Orthostatic Stress Tests & Neurohormonal Changes

The results of the autonomic function testing are presented in Table 2. Both groups of nOH patients exhibited reduced sinus arrhythmia and Valsalva Maneuver ratios, consistent with parasympathetic dysfunction. Sympathetic nervous system impairment was demonstrated in both groups by: a significant decrease in SBP during phase II of Valsalva and failure to increase SBP during phase IV of Valsalva; inadequate increases in SBP during the cold pressor and handgrip tests; and exaggerated decreases in SBP during hyperventilation. All patients demonstrated profound reductions in SBP and DBP upon standing without significant differences between racial groups (P = 0.91 and P=0.61, respectively). Supine and standing norepinephrine levels were comparable between racial groups.

Table 2.

Autonomic Function Tests, Orthostatic Stress Tests & Neurohormonal Changes

Parameters	AA	NH-W	P-value	Healthy
Sinus Arrhythmia Ratio	1.07 ± 0.02	1.07 ± 0.01	0.950	1.37 ± 0.12
Valsalva Maneuver Ratio	1.16 ± 0.04	1.13 ± 0.01	0.314	1.54 ± 0.08
Valsalva Phase II ΔSBP, mmHg	−78 ± 10	−69 ± 4	0.424	−14.38 ± 5.0
Valsalva Phase IV ΔSBP, mmHg	−30 ± 9	−35 ± 2	0.710	18 ± 3.4
Hyperventilation ΔSBP, mmHg	−31 ± 13	−29 ± 3	0.965	0.12 ± 2
Cold Pressor ΔSBP, mmHg	−4 ± 1	4 ± 1	0.080	16 ± 3
Handgrip ΔSBP, mmHg	−2.3 ± 7	−1.4 ± 2	0.652	19 ± 5
ΔSBP, mmHg	−69 ± 10	−70 ± 4	0.930	−2 ± 3
ΔDBP, mmHg	−29 ± 6	−32 ± 3	0.514	0 ± 3
ΔHR, beats per min	16 ± 4	10 ± 1	0.254	−5 ± 2
Mean supine NE level, pg/mL	144.2 ± 61.53	135.8 ± 16.36	0.83	286.4 ± 36.67
Mean upright NE level, pg/mL	211 ± 88.90	233.5 ± 29.63	0.84	688.5 ± 61.18

Data are presented as mean ± SEM. Healthy values are form control patients in Autonomic Dysfunction Center Database at Vanderbilt University Medical Center. P-values calculated using Mann-Whitney test.

^*P = < 0.05, [non-Hispanic whites N=48–51 and AA N=8–9].

NH-W non-Hispanic whites, AA African Americans, ΔSBP change in systolic blood pressure, ΔDBP change in diastolic blood pressure, HR heart rate, NE norepinephrine

Plasma renin activity and aldosterone levels with corresponding positional changes are shown in Fig. 1. Renin activity significantly increased during upright posture in non-Hispanic whites but not in AA, (0.17 ± 0.02 to 0.54 ± 0.11 ng/mL/hr; P =0.001 vs. 0.16 ± 0.04 to 0.20 ± 0.07 ng/mL/hr; P=0.374, respectively). The subjects in the healthy group demonstrated an increase in positional plasma renin activity from 0.24 ± 0.08 to 0.69 ± 0.33 ng/mL/hr; P=0.123 (Fig. 1A). Non-Hispanic white subjects showed a significant percent increase in renin activity compared to AA (295 ± 88% vs. 13 ± 13%, P =0.0027). A renin activity less than or equal to 0.2 mg/mL/hr was observed in 56% of AA (supine and upright), 50% of non-Hispanic whites in supine position, and 71% of non-Hispanic whites in upright position suggesting suppression of renin activity. The healthy group recorded a 112 ± 60% increase in renin activity during postural maneuvers (Fig. 1B).

Fig 1.

Mean positional plasma renin activity and aldosterone level with respective positional percent difference

Mean positional plasma renin activity and aldosterone level in AA (N=6), non-Hispanic White subjects (N=51), and healthy subjects (N=8) with corresponding positional percent difference. The increase in mean plasma renin activity and aldosterone were more pronounced in the non-Hispanic white population. P-values calculated using paired t-test. Bars represent ± 1 SEM. AA African Americans, NH-W non-Hispanic whites, Sup supine, Up upright

Similarly, aldosterone levels significantly increased in non-Hispanic whites but not in AA subjects during postural changes (3.79 ± 0.46 to 8.33 ± 0.96 ng/dL; P <0.0001 vs. 2.80 ± 0.92 to 4.22 ± 1.48 ng/dL; P=0.226, respectively). Positional aldosterone increased markedly from 1.64 ± 0.34 to 5.68 ± 1.12 ng/dL in the healthy population (Fig. 1C). Although it is not statistically significant, non-Hispanic whites showed a trend indicating an increase in percentage change of aldosterone to AA (188 ± 27 % vs. 59 ± 38 %; P=0.082). A 295 ± 92.0 % increase in positional aldosterone was demonstrated in the healthy subjects (Fig. 1D).

Discussion

The main finding from this study was that despite similar baseline clinical characteristics and hemodynamic autonomic profiles, AA patients with nOH exhibited significant neurohormonal differences in the renin-angiotensin aldosterone system (RAAS), which persisted during orthostatic hypotension. More specifically, AA subjects with autonomic failure exhibited reduced upright renin activity and plasma aldosterone levels compared to non-Hispanic white subjects.

The RAAS serves as a significant contributor to blood pressure regulation and the development of essential hypertension in humans [23]. It acts mainly through angiotensin II stimulation of AT₁ receptors to trigger vasoconstriction, cause baroreflex dysfunction, and stimulate aldosterone release to promote sodium and water retention [15]. Interestingly, initial studies showed the RAAS has little influence on blood pressure regulation in patients with autonomic failure [15]. This finding has been supported by low to undetectable plasma renin activity in autonomic failure patients, reduced renin response to postural and pharmacologic challenges, and loss of renin immune reactive cells in autopsied kidneys [16]. Recently, however, Arnold et. al. reported that levels of angiotensin II independently of plasma renin activity were elevated and contribute to supine hypertension in autonomic failure [17].

The present study demonstrates that among patients with autonomic failure and nOH, AA patients have lower plasma renin activity. Similarly, during the postural tests, the percent increase and total upright plasma renin activity were suppressed in AA but not in non-Hispanic whites with nOH. Interestingly, it has been noted in multiple studies with normotensive and hypertensive subjects, that plasma renin activity is reduced in subjects of African ancestry compared to European ancestry or Hispanics [18]. Studies suggest that a reduced rate of renin secretion is the most likely cause, but the exact mechanisms remain unknown [18]. Differences in renal sodium handling result from genetic variation in the renal epithelial sodium channel. Sodium retention drives the reduction in renin secretion to act as a corrective mechanism to maintain sodium homeostasis [18]. While the present study was not designed to determine the precise cause of low renin activity, taken with the results of these other studies, it could be possible that sodium retention in our AA patients is causing complete suppression of any residual renin secretion during positional changes that still occur in white patients with autonomic failure. This present study also supports that the racial differences in upright renin activity was not due to variations in sympathetic stimulation of juxtaglomerular cells. Sympathetic stimulation of the juxtaglomerular cells is a primary mechanism of secreting renin [18]. Since both groups had similar upright norepinephrine levels, it supports no difference in sympathetic activity while standing. In addition to salt retention, a potential mechanism of dissimilarities in upright renin activity between AA and non-Hispanic whites with nOH could be due to variances in local actions of nitrous oxide and prostanoids, which increase renin release [19]. These fundamental difference in renin levels between races could potentially be detrimental in AA patients because upright active renin triggers the generation of angiotensin, which supports blood pressure through its direct vasoconstrictive effect [20].

The present study showed decreased upright and blunted increase in aldosterone levels in AA when compared to non-Hispanic whites. Since the downstream RAAS pathways are intact in autonomic failure, aldosterone levels are typically normal in patients with autonomic failure [15]. While several studies have investigated the racial differences in hypertension, aldosterone levels, and downstream effects of RAAS signaling, results remain inconclusive. In contrast to our results, one study found that among hypertensive patients, AA subjects had higher standing plasma aldosterone levels (9.2 ± 0.7 ng/dL vs. 7.3± 0.6, respectively; P< 0.05) compared to white French-Canadian patients. They also showed positive correlations between standing aldosterone levels and nighttime SBP (r =0.30; P<0.01), SBP (r=0.39; P<0.001), left ventricular mass (r=0.36; P<0.001), posterior wall thickness (r=0.33; P<0.01), and interventricular septal thickness (r=0.26; P<0.05) in AAs [21]. Consistent with our results, some studies have shown lower aldosterone production among AAs [22–24], which is proposed to be caused by increased sodium retention suppressing the RAAS cascade in AAs [25]. Interestingly, one study that found low aldosterone levels among AA children and adults also showed increased aldosterone sensitivity in AA patients, which may offset the low serum concentration [25]. In this same study, the effect of aldosterone on SBP was enhanced as plasma aldosterone concentration increased and as plasma renin activity decreased, an effect exclusive to AA [25].

Our study showed similar occurrence of supine hypertension in AA and non-Hispanic whites with nOH. It is worth noting that our sample size was small; the reported prevalence of supine hypertension in autonomic failure was ~50% in previous studies [15]. In contrast, 67% of AA patients had supine hypertension in this cohort. It could be possible that salt retention may contribute to supine hypertension in this population, and a low salt diet in addition to short anti-hypertensive agents could be indicated in refractory AA patients. A study by Arnold et. al. showed that eplerenone was effective at reducing supine hypertension in autonomic failure patients with a low renin activity [26].

Clinical research studies have historically been biased towards studying large cohorts of non-Hispanic white men. Data on AA patients in general is quite limited, and studies of AA subjects with nOH are even more limited as nOH was thought to preferentially affect older non-Hispanic white males. This study provides a valuable characterization of autonomic profiles of AA patients with nOH and compares their results to non-Hispanic whites with nOH. Renin suppression, previously reported in AAs, persist in those with severe autonomic failure, and can potentially contribute to postural changes and supine hypertension. In cases of refractory hypertension in AAs with nOH, the use of non-pharmacologic therapeutic intervention such as a low salt diet may improve blood pressure.

Limitations

Potential limitations to this study include small samples sizes, especially in the AA group, and unequal distribution of neurodegenerative diseases. Enrolling a larger number of patients with higher numbers of MSA, PAF, and PD which would allow detection of potential pathophysiological differences between racial groups and variability between neurodegenerative disease subtypes. Another limitation is that the study only targeted specific differences in the African descendant population of North America, hence the significance and transferability to other populations is also limited.

The AA group was mainly composed of PAF patients with few or no PD or MSA patients, which limits the generalizability of these results to nOH patients with other forms of primary autonomic failure. In addition, not all of the patients had plasma renin activity and aldosterone levels measured (67% of AA) or completed autonomic testing (85–91% of non-Hispanic whites, depending on the test), limiting the power of the study. One AA subject’s aldosterone and plasma renin activity levels were considered an outlier and excluded in data analysis because the subject was sequentially diagnosed with primary hyperaldosteronism secondary to adrenal hyperplasia.