About the Program

  • Nicholas L. DePace
  • Joseph Colombo


Cellular energy production from mitochondria via the citric acid cycle and the electron transport chain is fundamental to health and wellness and life itself. Glucose is the molecule that fuels life, in the presence of oxygen, via cellular respiration, and ATP is the energy molecule that stores and transfers energy to where it is needed. Sufficient levels of cellular respiration are required for health and wellness. A lack of ATP can cause autonomic (P&S) and mitochondrial dysfunction, significantly effecting quality of life (QoL). Typically as ATP production decreases, free radical (including reactive oxygen species) production increases, affecting both mitochondrial and P&S health. The levels of P&S dysfunction include advanced autonomic dysfunction (AAD), also known as diabetic autonomic neuropathy (DAN, if the patient is diagnosed with diabetes), involving morbidity risk, and cardiovascular autonomic neuropathy (CAN) involving mortality risk. Normal system functions may generate oxidants (e.g., free radicals and reactive oxygen species). A small amount of oxidants are actually helpful to the body, especially the immune system where they are used to “burn out” infections (i.e., bacterial, viral, mold, and mildew). There are many adverse environmental and lifestyle sources of oxidants as well, including stress and disease. Too many oxidants lead to disorders, including atherosclerosis, autonomic neuropathy, and mitochondrial dysfunction, and the diseases that often follow those disorders. All in all, it is easy to overwhelm the body with oxidants. This is the basis for the need to have as large an antioxidant pool as possible, both from a healthy diet and from supplements. As people age or become ill, the naturally occurring antioxidant-oxidant ratio declines, and diet becomes not enough, requiring supplements to help establish and maintain healthy antioxidant-oxidant ratios.


Adenosine triphosphate (ATP) Advanced autonomic dysfunction (AAD) Antioxidants Antioxidant-oxidant ratio Cardiovascular autonomic neuropathy (CAN) Citric acid cycle Diabetic autonomic neuropathy (DAN) Electron transport chain Free radicals Minerals Mitochondria Mitochondrial dysfunction Morbidity risk Mortality risk Parasympathetic and sympathetic nervous systems Vitamins 


  1. 1.
    Colombo J, Arora RR, DePace NL, Vinik AI. Clinical autonomic dysfunction: measurement, indications, therapies, and outcomes. New York: Springer Science + Business Media; 2014.Google Scholar
  2. 2.
    Vinik A, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Vinik AI, Maser RE, Nakave AA. Diabetic cardiovascular autonomic nerve dysfunction. US Endocr Dis. 2007;2:2–9.Google Scholar
  4. 4.
    Jay SJ. Orthostatic hypotension and chronic fatigue syndrome. JAMA. 2001;285(11):1441–3. Scholar
  5. 5.
  6. 6.
    Zhang ZW, Cheng J, Xu F, Chen YE, Du JB, Yuan M, Zhu F, Xu XC, Yuan S. Red blood cell extrudes nucleus and mitochondria against oxidative stress. IUBMB Life. 2011;63(7):560–5. Scholar
  7. 7.
    Fillingame RH, Angevine CM, Dmitriev OY. Coupling proton movements to c-ring rotation in F(1)F(o) ATP synthase: aqueous access channels and helix rotations at the a-c interface. Biochim Biophys Acta. 2002;1555(1–3):29–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Kennedy DO. B vitamins and the brain: mechanisms, dose and efficacy – a review. Nutrients. 2016;8(2):68. Scholar
  9. 9.
    Tobias H, Vinitsky A, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J. Autonomic nervous system monitoring of patients with excess parasympathetic responses to sympathetic challenges – clinical observations. US Neurol. 2010;5(2):62–6.CrossRefGoogle Scholar
  10. 10.
    Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J. Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities. J Diabetes Sci Technol. 2008;2(4):568–71.CrossRefGoogle Scholar
  11. 11.
    Nanavati SH, Bulgarelli RJ, Vazquez-Tanus J, Ghosh-Dastidar S, Colombo J, Arora RR. Altered autonomic activity with atrial fibrillation as demonstrated by non-invasive autonomic monitoring. US Cardiol. 2010;7(1):47–50.Google Scholar
  12. 12.
    Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994;90(2):878–83.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Maser R, Mitchell B, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes, a meta-analysis. Diabetes Care. 2003;26(6):1895–901.PubMedCrossRefGoogle Scholar
  14. 14.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553–79.PubMedCrossRefGoogle Scholar
  15. 15.
    Curtis BM, O’Keefe JH. Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight. Mayo Clin Proc. 2002;77:45–54.PubMedCrossRefGoogle Scholar
  16. 16.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and diagnosing heart disease. “A clinical perspective”. Heart Int. 2014;9(2):37–44.; published online 12/5/2014 12:29:58 PM.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    DePace NL, Mears JP, Yayac M, Colombo J. Cardiac autonomic testing and treating heart disease. “A clinical perspective”. Heart Int. 2014;9(2):45–52.; published online 11/19/2014 1:16:08 PM.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bullinga JR, Alharethi R, Schram MS, Bristow MR, Gilbert EM. Changes in heart rate variability are correlated to hemodynamic improvement with chronic CARVEDILOL therapy in heart failure. J Card Fail. 2005;11(9):693–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Fatoni C, Raffa S, Regoli F, Giraldi F, La Rovere MT, Prentice J, Pastori F, Fratini S, Salerno-Uriarte JA, Klein HU, Auricchio A. Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure. J Am Coll Cardiol. 2005;46(10):1875–82.CrossRefGoogle Scholar
  20. 20.
    Fathizadeh P, Shoemaker WC, Woo CCJ, Colombo J. Autonomic activity in trauma patients based on variability of heart rate and respiratory rate. Crit Care Med. 2004;32(5):1300–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen JY, Fung JW, Yu CM. The mechanisms of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(Suppl 3):S2–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Copie X, Lamaison D, Salvador M, Sadoul N, DaCosta A, Faucher L, Legal F, Le Heuzey JY, VALID Investigators. Heart rate variability before ventricular arrhythmias in patients with coronary artery disease and an implantable cardioverter defibrillator. Ann Noninvasive Electrocardiol. 2003;8(3):179–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Alter P, Grimm W, Vollrath A, Czerny F, Maisch B. Heart rate variability in patients with cardiac hypertrophy – relation to left ventricular mass and etiology. Am Heart J. 2006;151(4):829–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Debono M, Cachia E. The impact of cardiovascular autonomic neuropathy in diabetes: is it associated with left ventricular dysfunction? Auton Neurosci. 2007;132(1–2):1–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Just H. Peripheral adaptations in congestive heart failure: a review. Am J Med. 1991;90:23S–6S.PubMedCrossRefGoogle Scholar
  26. 26.
    Nakamura K, Matsumura K, Kobayashi S, Kaneko T. Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res. 2005;51(1):1–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Manfrini O, Morgagni G, Pizzi C, Fontana F, Bugiardini R. Changes in autonomic nervous system activity: spontaneous versus balloon-induced myocardial ischemia. Eur Heart J. 2004;25(17):1502–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Clarke B, Ewing D, Campbell I. Diabetic autonomic neuropathy. Diabetologia. 1979;17:195–212.PubMedCrossRefGoogle Scholar
  29. 29.
    Litchman JH, Bigger JT Jr, Blumenthal JA, et al. Depression and coronary heart disease recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation. 2008;118:1768–75.CrossRefGoogle Scholar
  30. 30.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13 (Printed in Great Britain). Scholar
  31. 31.
    Cadenas E, Davies KJA. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3–4):222–30.PubMedCrossRefGoogle Scholar
  32. 32.
    National Institute of Standards and Technology. NIST -
  33. 33.
    Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair. 2008;1:5; 1–58.
  34. 34.
    Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO. Oxygen poisoning and X-irradiation: a mechanism in common. Science. 1954;119:623–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Gerschman R, Gilbert DL, Nye SW, Fenn WO. Influence of x-irradiation on oxygen poisoning in mice. Proc Soc Exp Biol Med. 1954;86(1):27–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 4th ed. Oxford: Oxford University Press; 2007.Google Scholar
  37. 37.
    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of aging. Nature. 2000;408:239–47.PubMedCrossRefGoogle Scholar
  38. 38.
    Dickinson BC, Chang CJ. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol. 2011;7(8):504–11.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Dröge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82(1):47–95.PubMedCrossRefGoogle Scholar
  40. 40.
    Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004;3(3):205–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Finkel T, Serrano M, Blasco MA. The common biology of cancer and aging. Nature. 2007;448(7155):767–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298–300.PubMedCrossRefGoogle Scholar
  43. 43.
    Harman D. Free radical theory of aging. Mutat Res. 1992;275:257–66.CrossRefGoogle Scholar
  44. 44.
    Apel K, Hirt H. Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol. 2004;55:373–99.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rhee SG. Cell signaling. H2O2, a necessary evil for cell signaling. Science. 2006;312(5782):1882–3.PubMedCrossRefGoogle Scholar
  46. 46.
    Kagan VE, Quinn PJ. Toward oxidative lipidomics of cell signaling. Antioxid Redox Signal. 2004;6(2):199–202.PubMedCrossRefGoogle Scholar
  47. 47.
    West JD, Marnett LJ. Endogenous reactive intermediates as modulators of cell signaling and cell death. Chem Res Toxicol. 2006;19(2):173–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Rodella LF, Favero G. Atherosclerosis and current anti-oxidant strategies for atheroprotection. Curr Trends Atherogenesis. 2012 (InTech, Open Access). Scholar
  49. 49.
    Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340:115.PubMedCrossRefGoogle Scholar
  50. 50.
    Greenland P, Gidding SS, Tracy RP. Commentary: lifelong prevention of atherosclerosis: the critical importance of major risk factor exposures. Int J Epidemiol. 2002;31:1129–34. Scholar
  51. 51.
    Krumova K, Cosa G. Overview of reactive oxygen species. In: Nonell S, Flors C, editors. Singlet oxygen: applications in biosciences and nanosciences, vol. 1. Cambridge: RSC Publishing; 2016. Scholar
  52. 52.
    Nathan C, Cunningham-Bussel A. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol. 2013;13(3):349–61.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Nathan C, Ding A. SnapShot: reactive oxygen intermediates (ROI). Cell. 2010;140(6):951.PubMedCrossRefGoogle Scholar
  54. 54.
    Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. 2011;111(10):5944–72.PubMedCrossRefGoogle Scholar
  55. 55.
    D’Autreaux B, Toledano MB. ROS as signaling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8(10):813–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Nishii W, Kukimoto-Niino M, Terada T, Shirouzu M, Muramatsu T, Kojima M, Kihara H, Yokoyama S. A redox switch shapes the Lon protease exit pore to facultatively regulate proteolysis. Nat Chem Biol. 2015;11(1):46–51.PubMedCrossRefGoogle Scholar
  57. 57.
    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of aging. Nature. 2000;408(6809):239–47.PubMedCrossRefGoogle Scholar
  58. 58.
    Stadtman ER. Protein oxidation and aging. Free Radic Res. 2006;40(12):1250–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Niki E, Noguchi N. Dynamics of antioxidant action of vitamin E. Acc Chem Res. 2004;37(1):45–51.PubMedCrossRefGoogle Scholar
  60. 60.
    Caro P, Gomez J, Lopez-Torres M, Sanchez I, Naudiand A, et al. Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver. Rejuvenation Res. 2008;11:621–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Seals DR, Edward F. Adolph distinguished lecture: the remarkable anti-aging effects of aerobic exercise on systemic arteries. J Appl Physiol. 2014;117(5):425–39. Scholar
  62. 62.
    Adly AAM. Oxidative stress and disease: an updated review. Res J Immunol. 2010;3:129–45.CrossRefGoogle Scholar
  63. 63.
    Cardinali DP. Autonomic nervous system: basic and clinical aspects. Cham: Springer International Publishing AG; 2018.CrossRefGoogle Scholar
  64. 64.
    Menotti A, Keys A, Blackburn H, Kromhout D, Karvonen M, Nissinen A, Pekkanen J, Punsar S, Fidanza F, Giampaoli S, Seccareccia F, Buzina R, Mohacek I, Nedeljkovic S, Aravanis C, Dontas A, Toshima H, Lanti M. Comparison of multivariate predictive power of major risk factors for coronary heart diseases in different countries: results from eight nations of the Seven Countries Study, 25-year follow-up. J Cardiovasc Risk. 1996;3(1):69–75.PubMedCrossRefGoogle Scholar
  65. 65.
    Menotti A, Seccareccia F, Blackburn H, Keys A. Coronary mortality and its prediction in samples of US and Italian railroad employees in 25 years within the Seven Countries Study of cardiovascular diseases. Int J Epidemiol. 1995;24(3):515–21.PubMedCrossRefGoogle Scholar
  66. 66.
    Toshima H, Koga Y, Menotti A, Keys A, Blackburn H, Jacobs DR, Seccareccia F. The Seven Countries Study in Japan. Twenty-five-year experience in cardiovascular and all-causes deaths. Jpn Heart J. 1995;36(2):179–89.PubMedCrossRefGoogle Scholar
  67. 67.
    Kostka T, Drai J, Berthouze SE, Lacour JR, Bonnefoy M. Physical activity, aerobic capacity and selected markers of oxidative stress and the anti-oxidant defense system in healthy active elderly men. Clin Physiol. 2000;20(3):185–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Santos-Parker JR, LaRocca TJ, Seals DR. Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv Physiol Educ. 2014;38(4):296–307. Scholar
  69. 69.
    Seals DR, Edward F. Adolph Distinguished Lecture: the remarkable anti-aging effects of aerobic exercise on systemic arteries. J Appl Physiol. 2014;117(5):425–39. Scholar
  70. 70.
    Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S, INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):953–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicholas L. DePace
    • 1
  • Joseph Colombo
    • 2
  1. 1.Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS CenterSewellUSA
  2. 2.TMCAMS, Inc.Franklin Cardiovascular Associates, PA and Autonomic Dysfunction and POTS CenterRichboroUSA

Personalised recommendations