The Feasibility of Blood Pressure Control with Autonomic-Assisted Hypertension Therapy Versus JNC 8 Therapy

Background: Over one billion people have Hypertension (HTN); mortality and morbidity are increasing. The Parasympathetic and Sympathetic (P&S) nervous systems prominently affect the onset and progression of HTN, yet P&S measures are not used to assist in management. Our objective was to determine the feasibility of HTN control using P&S-guided to JNC 8 HTN therapy. Methods: 46 uncontrolled HTN patients were randomized prospectively to P&S-assisted management, adjusting JNC 8 therapy using the ANX 3.0 Autonomic Monitor and adding (r) Alpha Lipoic Acid (Group 1) vs. JNC 8 (Group 2). Results: The two Groups were similar in: 1) age (mean 66 vs. 70 y/o for Groups 1 and 2, respectively; 2) initial resting home Blood Pressure (BP, Group 1 mean=162/90 mmHg vs. Group 2 mean=166/87 mmHg, 3) initial resting office BP Group 1 mean=151/75 mmHg vs. Group 2 mean=155/73 mmHg, and 4) ethnicity. Upon follow-up (mean=8.35 mo.): 1) mean resting home BPs were 145/77 mmHg (Group 1, 74% of patients at JNC 8 goal) vs. 155/83.5 mmHg (Group 2, 30.4% at JNC 8 goal), and 2) mean resting office BPs were 138/71 mmHg (Group 1) vs. 146/65 mmHg (Group 2). At the study’s conclusion, Group 1 Sympathetic tone was lower than that for Group 2 both at rest and upon standing, and Group 1 Parasympathetic tone was higher than that for Group 2 both at rest and upon standing. Conclusion: P&S-assisted HTN therapy is feasible, resulting in improved BP control, through healthier P&S tone on fewer prescription medications.

patients were under standard care based on the Eighth Joint National Committee (JNC-8) guidelines. At baseline, all patients recruited: 1) Were treated but uncontrolled HTN (unmet JNC goals) patients with any abnormality in P-and/or S-tone regardless of all other vital characteristics, 2) Signed informed consent, and 3) Were randomly, prospectively assigned to P&S-assisted therapy (Group 1) or JNC 8-guided only therapy (Group 2).  Each monitoring event recorded BP after 5 minutes of quiet sitting and the data were averaged upon entry. Three days of b.i.d BPs were averaged 2 months of adding (r)-ALA in Group 1, in order to allow it to take full effect and monthly thereafter, whereas BPs were repeated 2 weeks after entry in Group 2 and monthly afterwards. Physician measured BPs were never used in this unblinded trial and doses of antihypertensive medications, along with changes, were per JNC 8 guidelines in both groups; only the choice of medication, the use of alpha lipoic acid, and the frequency of medication change (less frequent in Group 1 since alpha lipoic acid requires at least 2 months for full effect, thereby excluding bias in favor of Group 1) differed Blood pressure goals were identical: patient recorded home BPs that would meet JNC goals. Office P&S testing measurements were taken with the ANX 3.0 autonomic monitor (TMCAMS, Inc., Atlanta, GA, USA, formerly ANSAR Medical Technologies, Inc., and Philadelphia, PA, USA). P&S activity were computed simultaneously and independently based upon concurrent, continuous time-frequency analyses of Respiratory Activity (RA) and Heart Rate Variability (HRV) [17][18][19][20][21]. P-activity (measured as the Respiratory Frequency area (RFa) is defined as the spectral power within a 0.12 Hz-wide window centered on the Fundamental Respiratory Frequency (FRF) in the HRV spectrum. FRF is identified as the peak spectral mode of the time-frequency analysis of RA.

P&S-Guided
Effectively, FRF is a measure of vagal outflow as it affects the heart (a measure of cardio-vagal activity). S-activity (measured as the Low Frequency area (LFa) is defined as the remaining spectral power, after computation of RFa, in the low-frequency window (0.04-0.15 Hz) of the HRV spectrum. High Sympathovagal Balance (SB=LFa/RFa) is defined as a resting ratio >2.5, established in our 483 patient study [9]. P&S activity was recorded from 5 mins of quiet sitting (normal ranges for both P&S at rest, including sitting, is defined as 0.5-10 beats/minute2 [bpm2]). The reported average SB is the average of the ratios of 4 second samples during sitting, not a ratio of the averages. Cardiac Autonomic Neuropathy (CAN) is defined as critically low, resting P-activity, RFa of <0.10 bpm2.
High SB and CAN define a high risk of mortality, including: acute coronary syndromes, congestive heart failure or ventricular tachycardia/fibrillation alone or as a composite endpoint [9]. With challenge (e.g., head-up postural change or standing), a normal Sresponse (LFa) is defined as up to a 400% increase with respect to rest (e.g., sitting) and a normal P-response (RFa) is a decrease with respect to rest. Follow-up BPs and P&S measures were recorded 2 months after therapy adjustment in Group 1, whereas BPs were rechecked 2-4 weeks after adjustments in Group 2. Statistical analyses were performed in SPSS v22.0. Dichotomous data were analyzed using the chi-square test. A pvalue of 0.05 or less was significant. Student t-tests as two-tailed with equal variance.

Results
Although the two groups had similar initial BPs, home BP control was more normalized in the P&S-assisted patients. As a result, with P&S-Assisted therapy, all but one (5 of 6 or 83%) of the Group 1 patients with low resting S-tone improved vs. 9 of 17 (53%) of similar Group 2 patients, p<0.001. These improvements also reduced the symptoms of fatigue and orthostatic hypotension in these low resting Stone patients. P-tone directly and indirectly affects S-tone and thereby may affect BP. Low-resting P-tone may result in high resting S-tone, since P-and S-tone typically variate reciprocally. High S-tone increases BR activity, attempting to lower BP; low P-tone does the opposite. These opposing actions may increase difficulty in controlling BP in hypertensives. Initially, 7 of 23 (30%) Group 1 patients had low resting P-tone (<0.5 bpm2), vs. 15 of 23 (65%) Group 2 patients (p<0.001).  High SB is a measure of (relatively) high resting S-tone. Combining the resting S-tone results and CAN (very low P-tone) results, these findings support the hypothesis that lower S-tone lowers the risk of CAN [9]. At the end of the study, Group

Discussion
This study demonstrates improved HTN BP control on fewer prescriptions using adjunctive (r)-ALA in Group 1 (74% of patients at JNC 8 goal vs. 30.4% of Group 2 patients, p<0.001). We and others have shown (r)-ALA can reduce resting BP and in this study concomitantly may assist lowering standing BP [16,22]. Superficially, the medication administration profiles do not explain the improvement in BP control, as more Group 2 patients took beta blockers, CCBs, and ARB/ACEIs. It may be that (r)-ALA's favorable P&S effects significantly contributed to better HTN control via S-and P-dependent as well as its ANS-independent endothelial effects. Two Group 1 patients normalized BP solely by taking (r)-ALA.
Based upon P&S measures, 17% of Group 1 patients had a change of drug class vs. 9% in Group 2. This likely was also beneficial. High SB corrected in 71% of Group 1 patients vs. none in Group 2, contributing to lowering HTN [22]. Amlodipine increases SB, while beta blockers and clonidine decrease SB; beta-blockers and ARB/ACEIs improve BRS; and non-dihydropyridine CCBs decrease BRS [22][23][24][25][26][27]. (r)-ALA is a powerful natural antioxidant that improves P&S function including BRS, nitric oxide levels, and endothelial dysfunction [15,16,22,28]. Sympathetic Withdrawal upon standing results in compensatory mechanisms to preserve perfusion of vital organs that include increasing S-tone, both supine and sitting.
This exacerbates HTN, thereby causing its control to be more difficult. Sympatholytics, therefore, can worsen SW (only clonidine has a minimal adverse effect as it increases BRS [24,25,29]. Group 1 patients significantly improved SW. This is consistent with improved BRS, probably by (r)-ALA and higher doses of Lisnopril and Losartan. Pexcess (PE) upon standing is indicative of ANS dysfunction, and 9 of 23 (39%) of Group 1 vs. 5 of 23 (22%) of Group 2 patients initially displayed PE. PE may also trigger compensatory measures, including secondary Sexcesses that increase BP.
The central alpha action of Carvedilol, Low Dose Serotonin Reuptake Inhibitors (SSRI), as well as Tricyclics (TC) may help to reduce PE. One Group 1 patient normalized PE and HTN with addition of (r)-ALA alone.
Resting P&S measures were utilized in choosing medications as follows.
If P&S balance (as measured by SB) was normal, then any antihypertensive was prescribed.
If SB was high due to a relative, resting S-excess), then sympatholytics were chosen or adjusted. If SB was high due to low P, then sympatholytics were avoided and an ARB/ACEI and/or Diltiazem were chosen or adjusted. High dose (r)-ALA may increase resting P-activity and thereby lower SB. Upon standing, if SW was absent, then any antihypertensive was prescribed. If SW was demonstrated, then sympatholytics were avoided (excepting Clonidine) as was Diltiazem and Amlodipine, Hydralazine and/or high dose (r)-ALA prescribed. Diuretics were utilized only for dependent edema, since intravascular volume needed to be maintained. Low dose ARB/ACEI also might be prescribed. If PEpresented, again intravascular volume should be preserved, so diuretics were avoided. Since an increase in S-activity is a compensatory mechanism to combat orthostasis, sympatholytics were avoided (except low dose carvedilol whose central alpha action reduces P-tone and possibly clonidine). Amlodipine is a good choice only if S-tone isn't high, since it increases S-activity.
Adjunctive low dose TC or SSRI would have useful to reduce P-activity, but we confined our therapy to traditional anti-hypertensives. The uncoupling of P&S function to Rs in HTN results in variable P&S profiles. Anti-hypertensives have variable P&S effects. Consequently, knowledge of S-and P-tone is essential for choosing the best antihypertensive drugs and (r)-ALA enhances their effectiveness, given (r)-ALA's ANS antioxidant effect which reduces ANS dysfunction secondary to the increased oxidative stress associated with HTN, chronic diseases and the aging process (Tables 3, 4 and 5 are illustrative).     Table 3).

Conclusions
P&S-assisted treatment of HTN, with adjunctive (r)-ALA for dysautonomia is feasible and results in more normalized BP control within one year. Our hope is that reduced long-term medication costs, mortality, and morbidity will follow if BP control is sustained. A randomized, prospective clinical outcome study should be dome.

Limitations
These results are short-term, single center, in 46 patients. Our accent was specifically lowering SB. Reducing standing PE with low dose TCs or SSRIs could have improved BP control further.