(r)Alpha Lipoic Acid Is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone (2024)

Abstract

Keywords: α-lipoic acid, orthostatic hypotension, autonomic nervous system, parasympathetic nervous system, sympathetic nervous system

Chronic orthostatic hypotension (OH, defined as fall of systolic blood pressure [BP] or diastolic BP ≥ 20/10 mm Hg within 3 minutes of standing still) is prevalent at any age, but mostly in the elderly¹in whom neurogenic orthostatic hypotension (NOH [such as low sympathetic (S) tone with head-up postural change (i.e., standing)]) is by far more common than venostasis or iatrogenic causes, with OH prevalence rates up to 30%.²OH is a common cause of lightheadedness in elderly or chronic disease patients and is one of the earliest, and arguably the most debilitating, symptom of autonomic dysfunction.³⁴

OH is associated with increased mortality in the elderly: hazard ratios of systolic BP OH: 1.69 to 2.04; diastolic BP OH: 2.2.⁵OH in diabetics can be an early manifestation of cardiac autonomic neuropathy, and possibly in nondiabetics and the elderly. Cardiac autonomic neuropathy increases mortality by 25 to 50% within 10 years,⁶and heart failure death or hospitalization is also high (hazard ratio 1.85).⁷Oxidative stress, regardless of the source (sugar acidosis, low antioxidant levels, psychosocial stress, lack of exercise, smoking, pollution, etc.), causes autonomic injury that precedes diabetic autonomic neuropathy. Autonomic injury affects all systems of the body. Oxidative and nitrosative stress damages the more sensitive tissues, including peripheral and central nerves, endothelial cells, immune cells, the microvasculature, and glomerular filtration structures. Therapies known to reduce oxidative stress are therefore recommended. α-lipoic acid (ALA), through its multiple antioxidant properties, has long been found to slow or stay the progression of autonomic injury.⁸⁹

The autonomic nervous system plays a critical role in BP regulation.¹⁰Since (r) ALA has been used in treating diabetic cardiac autonomic neuropathy, including orthostatic dysfunction and hypertension,^11121314we postulated it might improve NOH as well as orthostatic intolerance (OI) in nondiabetics, without causing or worsening hypertension or volume overload; as do most frequently used pharmacologic agents.¹⁵

As human longevity increases worldwide, OH will become increasingly problematic. Presently, most types of OH are treated similarly. Medications with hypotensive side effects are reduced or discontinued, compression hose for lower extremity edema, and occasional abdominal binders to increase venous return, fludrocortisone, increased oral fluid and salt intake to increase plasma volume, midodrine for vasoconstriction, and most recently droxidopa to increase norepinephrine levels.¹⁶Other medications are uncommonly used.¹⁷¹⁸However, many of these measures can cause or exacerbate pre-existing hypertension, or worsen congestive heart failure. Clearly, much more efficacious treatment is needed.

ALA is a naturally occurring substance, a powerful thiol antioxidant that restores and recycles vitamins A, C, E, and glutathione, enhancing their efficacy. ALA also improves hyperglycemia, endothelial dysfunction, nitric oxide levels; reduces nuclear factor kappa B activity, is essential for the function of certain oxidative enzymatic activities; and has been mainly used to treat diabetic dysautonomia.¹⁹It also suppresses neurologic intracellular accumulation of α-synuclein, the major cause of NOH in many neurologic diseases.²⁰²¹It exists as two enantiomers, with (r)ALA much more active than (s)ALA, and does not require a prescription. ALA treatment seems safe and effective (without hypertensive side effects or volume overload) for NOH or OI patients, even in nondiabetics. The purpose of this study is to demonstrate improvement in the symptoms of orthostatic dysfunction with r-ALA, including improved S and BP responses to head-up postural change (standing).

Methods

Using the ANX-3.0 Autonomic Monitor (ANSAR Medical Technologies, Inc., Philadelphia, PA), sympathetic- (S) and parasympathetic (P)-activity were computed simultaneously and independently based on concurrent, continuous, time frequency analysis of respiratory activity, and heart rate variability.^222324252627P activity measured as the respiratory frequency area (RFa) is defined as the spectral power within a 0.10 Hz-wide window centered on the fundamental respiratory frequency in the heart rate variability spectrum. Fundamental respiratory frequency is identified as the peak spectral mode from time-frequency analysis of respiratory activity. RFa is a measure of vagal outflow as it affects the heart. S activity (low frequency area [LFa]) is defined as the remaining spectral power in the low-frequency window (0.04–0.15 Hz) of the heart rate variability spectrum, after computation of RFa.

P- and S activity was recorded from a standard autonomic test, including (1) 5 minutes rest (seated), (2) 1 minute of breathing at 6 breaths/minute, (3) a series of 5 Valsalva maneuvers, including a 15 second Valsalva maneuver, and (4) a quick stand to 5 minutes of quiet standing. The average ratio of resting S to P activity (sympathovagal balance) reported was the average of the ratios recorded during the sampling period, not the ratio of the averages.²⁸

A cohort of 109 patients with low S tone upon standing was detected using the ANX -3.0, Autonomic Monitor, ANSAR Medical Technologies, Inc., Philadelphia, PA. From the cohort, 29 patients demonstrated NOH (change in (∆) standing BP ≥ −20/–10 mm Hg) and 60 patients demonstrated orthostatic intolerance (OI, ∆ standing systolic BP between –6 and –19 mm Hg). These 89 were given ALA orally: either 590 to 788 mg (r)ALA or 867 to 1,500 mg of the less expensive 50 to 50% mixture (r)ALA and inactive (s)ALA. Changes in their S- and P tone, and BPs, were compared with 20 control patients during mean follow-up of 2.28 years.

All 109 study patients had low S sitting or standing. The only change in patients' therapy was the addition of (r)ALA or ALA (a racemic mixture of (r)- and (s)ALA). Syncopal responders had no recurrence of syncope, otherwise response was defined as ∆ standing systolic BP < –6 mm Hg.

This study was approved by our Institutional Review Board, and all patients signed informed consent.

Results

Patient demographicsare listed inTable 1. In the OH Group (n = 29),¹there were no females in the 10 nonresponders;²there were more diabetics;³80% were prescribed midodrine, fludrocortisone, or desmopressin; and⁴20% were on beta-blockers. There were fewer patients with hypertension or congestive heart failure, but more with syncope. In the OI group (n = 60), there were fewer congestive heart failure patients, but more with syncope, fatigue, and headache.

Patient autonomics and BPsare listed inTables 2and​and3.3. In the OH group, pre-and post-treatment ∆ standing BP was –32/–9 mm Hg versus –29/–11 mm Hg in nonresponders, and –28/–6 mm Hg versus 0/+2 mm Hg in responders. In the OI group, pre- and post-treatment ∆ standing BP was −13/−19 mm Hg versus −12/+2 mm Hg in nonresponders, and −9/+1 mm Hg versus +6/+2 mm Hg in responders. Responders had higher S tone (Table 3). Regardless of the ∆ standing BP, (r)ALA reduced sitting BP in most patients. In the controls, there was no significant difference in ∆ standing BP (from a baseline of −13/−1 to a follow-up of −13/+3), and there was a decrease in S activity with follow-up.

Discussion

NOH is caused by failure of the baroreceptor reflex and/or too low S tone, usually as a result of neurologic intracellular α-synuclein production and aggregation.²⁰ALA suppresses this as an antioxidant, improving the baroreceptor reflex and S tone, in contrast to the commonly used medications, so it should affect healing of the disorder, rather than simply treating its symptoms. Furthermore, it uniquely reduces resting hypertension and endothelial dysfunction.^2930313233

Although only 28% of the patients were diabetic (Table 1), 59 of 89 (66% of all) patients responded to ALA. Sixteen of the 25 diabetics (64%) responded and 43 of 64 (67%) nondiabetics (p = ns), suggesting that ALA may be equally effective for all patients with orthostatic dysfunction. Nineteen of 29 (66%) NOH and 40 of 60 (67%) OI patients responded to ALA (p = ns), furthering the above suggestion.

(r)ALA raised LFa (S activity) in all patients except in OI nonresponders (Table 2). Treatment ∆ BP was related to pretreatment S activity. Those with the lowest sitting to standing change in S activity were the nonresponders (Table 3); perhaps droxidopa would be useful in these patients.

Responders had both a decrease in mean sitting BP (145/72–125/68 mm Hg, pre- to post-(r)ALA treatment, mean dose 643 mg/d or ALA 949 mg/d), and an increase in mean standing BP (120/70–129/71 mm Hg, pre- to post-treatment). This ∆ sitting BP indicates an improvement in resting hypertension and the ∆ standing BP indicates an improvement in orthostatic dysfunction. OI nonresponders demonstrated a +19 mm Hg (increase) in standing diastolic BP, which is vital in preserving coronary perfusion (Tables 1,​,2).2). In patients with coronary artery disease, a J-curve relationship has been reported between BP and major adverse cardiac events.³³Given this J-curve of coronary flow and since major adverse cardiac events increase at diastolic BPs < 60 to 70 mm Hg,³³the increase in diastolic BP in the OI nonresponder group could have been considered a positive OI response, but we defined a positive response as a standing decrease in only systolic BP less than −6 mm Hg, and the absence of syncope. Even though the OI nonresponders' standing systolic BP fell 6 mm Hg or more (an average fall of 12 mm Hg,Table 2), their diastolic BPs increased significantly (from a fall of 19 mm Hg to an increase of 2 mm Hg;p = 0.0068,Table 2). This improved outcome would raise the positive response rate to (r)ALA to 88% had we considered the J-curve of coronary perfusion,

Although previous human studies of the effect of ALA upon high BP have been mixed,³⁴it can reduce high BP, increase baroreceptor reflex afferent limb sensitivity, improve endothelial dysfunction, increase nitric oxide, and improve diabetic dysautonomia. In our 19 OH responders, mean ∆BP to standing from pre- to post-treatment was –28/–6 mm Hg (sitting to standing, pretreatment) to 0/+2 mm Hg (sitting to standing, post-treatment). To date, we know of no other pharmacologic treatment that both decreases resting hypertension and OH. Such treatment has the potential to reduce substantially major cardiovascular events such as stroke, congestive heart failure, myocardial infarction, and cardiovascular death (major adverse cardiac events), as well as therapeutic costs and side effects. Nausea, rare flushing, and biotin depletion are the only known side effects of (r)ALA or ALA, and are harmless and easily treatable.

In the 20 control patients, S activity decreased, although ∆ BP did not, possibly because their initial S activity was the highest of all groups. Regardless, the decrease in S activity may be the prelude to further decreases in BP, if therapy is not prescribed. Since S activity controls BP and BP changes with stand (and other activities), the persistent decrease in S activity with stand indicates that there is a continued drive to further decrease BP upon standing, exacerbating orthostatic dysfunction and the associated morbidity and mortality risks. Because these untreated patients' S activity might continue to fall, perhaps they should be started on (r)ALA or ALA.

Limitations

A larger, longer study that also determines if ALA reduces major adverse cardiac events in NOH, and whether progression of these conditions is slowed, is needed. Additionally, if there is a partial response to therapy, what should be done next? Certainly, adjusting other hypotensive medications without absolute indications would seem obvious. Finally, our definition of OI was arbitrary.

Conclusion

(r)ALA or ALA appears to safely improve NOH and OI by increasing standing S activity, as measured by LFa, and thereby standing BP responses to stand.

Funding Statement

FundingNo funding was provided.

Footnotes

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