Re-print: Maintenance (r) Alpha Lipoic Acid Reduces Sudden Cardiac Death in Geriatric Diabetes Mellitus II Patients

Background: Diabetes carries a two-fold risk of Sudden Cardiac Death (SCD). Diabetic Autonomic Neuropathy (DAN), often progressing to Cardiovascular Autonomic Neuropathy (CAN, critically low parasympathetic tone [P]), increases death 3.5-fold over 5 years, half sudden or nonrenal. Oxidative stress is a major cause of DAN. Also, increased sympathetic tone (S), High Sympathovagal Balance [SB>2.5] increases SCD risk. Objective: Dysautonomic diabetic II patients were treated with the antioxidant (r) Alpha Lipoic Acid (ALA), autonomic function followed, and Sudden Death (SD) compared to untreated patients. Methods: 133 patients (mean age 66y/o) with DAN or CAN, diagnosed using the ANX 3.0 Autonomic Monitor (Physio PS, Inc., Atlanta, GA) was offered (r)-ALA: 83 agreed (Group 1), and 50 refused (Group 2). P and S were remeasured up to 3 times/yr (mean f/u 6.31 yrs); SCDs were recorded. Results: A 43% Relative Risk Reduction (RRR) in SCD occurred with (r)ALA (25% SCD Group 1 vs. 44% SCD Group 2, p=0.0076). Initial to final patients with high SB or CAN were 21.7%-12% (p=0.010), 10.8%15.7% (p=0.045), Group 1 vs. 24%-22% (p=ns), 6%-12% (p=0.083), Group 2. Only Group 1 survivors increased mean resting P. The progressive increase in P’s decline, increasing CAN risk, in the other patients correlated with mortality (p<0.001) and (r) ALA dose. Initially, Group 1 had insignificantly less high SB (p=0.449) and significantly more CAN (p=0.013) vs. Group 2. Finally, Group 1 had significantly less high SB (p=0.0967) vs. Group 2, also improving to insignificantly more CAN (p=0.261). Conclusion: (r)-ALA was associated with a 43% RRR of SCD and favorable P and S changes.

In the 83 (r)-ALA patients (Group 1), P&S were recorded 2-3 mo. afterwards until maintenance dosage, then yearly. Non-(r)ALA patients (Group 2, refused (r)-ALA) were tested yearly. Exclusion criteria were (1) arrhythmia precluding HRV measurement, and (2) cancer within 5 yrs. The inclusion criterion was DM II with any abnormality of P or S. Informed consent was obtained for this open-label, un-blinded study. The cause of SD was determined from hospital records or death certificates. Out of hospital SCD was defined as pulse less SD of cardiac origin. Group 1 patients were subcategorized: survivors, Group AA; nonsurvivors Group AD. Group 2 (Controls): survivors, Group NA; nonsurvivors, Group ND. All patients took aspirin. All patients had Cardiovascular Autonomic Reflex Test (CART) w/o isometric grip (grip has only 25% sensitivity for CAN) [19]. DAN was defined as any abnormality of S or P, or high SB. CAN was defined as P<0.10bpm2, or 2 abnormalities of CARTs. Median follow-up was 5 yrs. Mean age was 66 y/o. There were 83 males, 50 females. Upon referral, rhythm assessment (Holters ± event monitors) were performed if clinically indicated: Groups AA 60%, AD 57.1%, NA 60.7%, ND 31.8%.

Demographics
Group AA vs. Group ND: Improved Group AA survival occurred despite Group ND having a normal final BMI (p=0.067), less HTN (p=0.021), greater use of Empagliflozin (p<0.100), Metformin (p<0.100), lower final A1C (p=0.034), and fewer males (p<0.100), all favoring less SCD in Group ND. DMII attenuates gender differences in SD [22]. Group ND was 3 yrs. Older (p=0.067) with more CAD (p<0.100); all were revascularized (normal myocardial perfusion stress tests). Fewer in Group AA took insulin (p<0.100). Initially, Group AA had 18.4% VT (1sustained) vs. 14.3% non-sustained in Group ND, p=0.3559.  In parallel, SCD patients experienced a dramatic 59.5% decrease in resting P in addition to SW. All P-and S-final values were lower in SCD, the lowest being resting P. Since HRV=S+P, HRV was lower in SCD (p<0.0001) mainly due to lower P.
Group ND, Non-Survivors without (r)-ALA: (Table 7) Initial resting BxLFa, resting BxRFa, were normal; SB high for age (but not >2.5 Final BxLFa decreased, p=0.100; BxRFa severely decreased, p=0.020. Two more patients (67%) developed CAN (p=0.020) in spite of initially good BxRFa. Group ND's initial standing P was normal, but S showed SW. Final average S-stand remained SW; P barely normalized. The Presponses as compared with the Group-AA are different (p=0.106).    (Tables 6&7): 10.5%, Group AD and 67.5%, Group ND (p=0.033); a higher risk of developing CAN. Final SB was >2.5 in both, which we have shown increases MACE 700% [18]. SB greater than 2.5 with CAN is particularly deadly in both Groups, and final average standing response was SW (impaired BRS), increasing SCD as well. BxLFa increased in Group AD (

Discussion
Administration of (r)ALA resulted in a 43% RRR of SCD, rather than the demographics that may have favored survival in Controls. Rapid separation of the SCD curves ( Figure 1)  It improves hyperglycemia, endothelial dysfunction, nitric oxide levels (protective against VT/VF, silent ischemia [37][38][39][40]), reduces nuclear kappa B, and is essential for certain mitochondrial oxidative enzymes. (r)ALA prevents diabetic-induced reduction of the afferent limb function of the baroreceptor reflex (BR) [41], reducing MACE. SW, found in 50% to 74% of patients, failed to correct in 88% of Group NA and all SCD patients. SW disappeared substantially only in Group AA, 59.7% reduced to 53.2%, p=0.097, decreasing SCD risk. The other most common, and most important, P&S finding was low resting P in 56% to 81% of patients, improving only in Group AA (initial 56%, final 9%; p=0.070), vs. Group NA (initial 29%, final 43%; p=0.098), and worsening most severely in Group ND patients, a 67% reduction in RFa vs. 10.5% reduction in Group AD (p=0.020).
CAN decreased 37.5% in Group AA vs. an increase of 67% in Group ND. 29% of Group AD had high SB vs. 50% in Group ND (p=0.037). More CAN in Group 2 increased mortality; high SB increased mortality risk in Group 1. Group 1's autonomic profiles generally stabilized or improved (HRV); Group 2's deteriorated, especially a 59.5% decrease in resting P, reducing Group 2's ability to combat VT/VF, silent ischemia, and life stresses. Standard deviations decreased over time, with the most decreases correlating with the (r)ALA dosage. The pleotropic effects of (r)ALA likely contributed to SCD reduction. Increased nitric oxide improves P&S, endothelial dysfunction, protects against VT/VF and silent ischemia [37][38][39][40]. Decreased nitric oxide levels prolong QTc [37]. Improved mitochondrial function should reduce SCD also [42]. Asymptomatic SW (BR dysfunction) was the most common presentation of DAN. Approximately 90% of patients had HTN, presumed to be essential (primary), not possibly secondary to DAN. Ultimately, CAN with, or without, dangerously high SB can develop while under our care. How simple it is to diagnose and treat dysautonomia early; how tragic it may be not to.