2nd The Milner Acetylcholine Place Protocol (MAP) for Management of Cardiac Dysrhythmias Jeremy Mikolai, ND, and Martin Milner, ND Background and Innovation this is achieved through a prolonged neurotransmitter which agonizes the “There are no naturally occurring refractory period that results from beta-1 adrenergic receptors of the heart; beta blockers,” Dr. Milner often says in increased cell permeability to potassium, it increases automaticity and contractility reference to the use of beta-1 adrenergic which increases the phase 4 portion of the by increasing the permeability of the receptor blockers (beta blockers) in the cardiac action potential. cells to calcium. Release of ACh in the treatment of arrhythmias and in control The ventricles of the heart are also supraventricular myocardium and from of the heart rate. “Nature doesn’t block affected by ACh, though the vagal the few parasympathetic fibers in the receptors,” Milner asserts. “It augments innervation of the ventricles is sparse. ventricles inhibits the release of NE from antagonist pathways. Acetylcholine is This occurs by virtue of the antagonistic sympathetic fibers. That NE inhibition ‘nature’s beta blocker.’” relationship between the sympathetic and prevents increased automaticity by the There are moments in a physician’s parasympathetic halves of the ANS. sympathetic ANS.3 career when he sees the biochemistry of Ventricular myocardium is heavily ACh in the human body is synthe sized a disease process in a whole new way. innervated by the sympathetic ANS. from acetyl-coenzyme A (acetyl-CoA) and Beginning in 2008, Dr. Milner revisited Norepinephrine (NE) is the dominant ➤ his study of the autonomic nervous system (ANS) control of heart rate; he considered the actions of beta blockers which inhibit sympathetic ANS stimulation of the heart. He considered acetylcholine (ACh), the neurotransmitter of the parasympathetic ANS, and its action on heart rate inhibition. He then developed an approach for using oral supplements to augment ACh production and release. This evolved into the Milner Acetylcholine Protocol (MAP) for management of cardiac dysrhythmias.1 Biochemical Plausibility The biochemical plausibility of the MAP is based on the ACh inhibitory effect on cardiac rate and dysrhythmias through several mechanisms. The sinoatrial (SA) node, the normal pacemaker of the heart, receives input from the 10th cranial nerve (CN X), the vagus nerve, via ACh. That effect on the SA node inhibits automaticity and slows the heart rate. This is achieved by hyperpolarization of the cells through increased potassium permeability, result- ing in slower spontaneous depolarization.2 The atrioventricular (AV) node of the heart also receives input from the vagus nerve via ACh. The effect slows or blocks conduction through the node. Again, Figure 1: Biosynthesis of ACh and Immediate Precursors TOWNSEND LETTER – FEB/MARCH 2013 BEST OF NATUROPATHIC MEDICINE 73 Management of Cardiac Dysrhythmias ➤ choline in a reaction catalyzed by the Choline deficient states may play can raise endogenous neurotransmitter enzyme choline acetyl transferase (CAT; a part in diseases and conditions levels. His work pertains primarily to Figure 1, p. 73). including liver disease and fatty serotonin and catecholamines, but Acetyl-CoA comes from any of several liver infiltration, neural tube defects, is applicable to ACh via analogous sources, including dehydrogenation methylation defects, hypertension, mechanisms. More importantly, the work of pyruvate, end products of fatty acid atherosclerosis, neurological disorders, of Hinz et al. has established that oral metabolism, or production of coenzyme inflammatory disorders, and cancer.7 precursor dosing leads to demonstrable A (CoA) from vitamin B5 which is then Population research has demonstrated clinical effects and improved patient acetylated before interacting with choline. that many groups do not achieve their outcomes.19–22 Pyruvate is the end product of aerobic AI of choline.6,8–11 For instance, there is The half-life of ACh is very short glycolysis. It can also be converted from evidence that only 2% of postmenopausal at 2 minutes. To ensure fidelity in lactate, the end product of anaerobic women reach their choline AI on a daily neuromuscular transmission, the body glycolysis. Pyruvate can then be converted basis.11 further enhances this breakdown of ACh to acetyl-CoA through the action of the Research has established that genetic enzymatically through acetylcholine pyruvate dehydrogenase complex. Acetyl- polymorphisms which alter choline esterase enzymes. While ACh is CoA then has several potential fates, all of or folate metabolism may increase reclaimed by reuptake at the synaptic which demand the transfer of acyl groups, an individual’s dietary requirement cleft, augmenting production and release including participation in the Krebs cycle, for choline. For instance, when to the extent necessary to inhibit cardiac in fatty acid synthesis, in the production of 5-methyltetrahydrofolate (5-MTHF) is automaticity will require the persistent ACh, and others.4 deficient due to a polymorphism (or availability of substrates for ACh Pantothenic acid (PA), vitamin B5, other reasons), the body depends on production, a problem that we will need is the initial substrate for de novo CoA betaine from choline for the conversion to address. synthesis. This five-step process requires of homocysteine to methionine.12 While we can find no evidence in the both pantothenate (ionized PA) and the Methionine is then converted to medical literature for the use of choline sulfur containing amino acid cysteine. S-adenosyl-methionine (SAMe), the major to address cardiac dysrhythmias, we can Pantethine is a derivative of PA and is methyl donor for one-carbon transfers in establish that the biochemical action the functional component of CoA in the the body.13 When choline is required as of ACh exerts control over the cardiac carrying of acyl groups. Pantethine is a methyl donor it is shunted away from rate and depolarization. The fact that composed of two pantethine molecules other biochemical processes. Therefore, supplementing oral choline raises levels of joined by a disulfide bond.5 greater demand for dietary choline may ACh in the CNS is long established in the Choline is an essential nutrient. be prevalent in the population based medical literature, as cited.17,18 Therefore, Humans reutilize choline and synthesize on genetic polymorphisms that are the biochemical and therapeutic it de novo, but in quantities insufficient prevalent.14–16 plausibility for the choline aspect of MAP to meet metabolic demand. Therefore, an is present. adequate intake of choline is necessary Therapeutic Plausibility Pantethine has been reported to have for health.6 The established adequate The therapeutic plausibility of utilizing antiarrhythmic action on experimental intake (AI) in adult men is 550 mg/day the ACh pathway in the treatment models of cardiac arrhythmias. In a and in adult women is 425 mg/day unless of cardiac dysrhythmias through study of a dog model of hypoxic cardiac pregnant (450 mg/d) or breast-feeding (550 supplementing oral precursors requires perfusion, administration of pantethine mg/d). Eggs are the richest dietary sources both that (1) oral supplementation be able was shown to significantly prolong the of choline, followed by animal protein to raise ACh levels in the neurons; and cardiac action potential and refractory sources, leaving vegans and several other (2) those increases demonstrate clinical period.23 While the mechanism of that groups at routinely inadequate daily effects. effect was not described, it is noteworthy intakes.7–10 A list of choline content in It is well established that the amount that this is the same action which ACh has foods can be found in the Micronutrient of ACh in the central nervous system on the supraventricular myocardial cells, Information Center article on choline from is directly affected by the oral intake as described above. the Linus Pauling Institute, Oregon State of choline. Studies and reviews which Research on rate models of cardiac University.7 date back to the late 1970s establish that function has demonstrated that the Choline is an essential substrate in the the synthesis of ACh in the brain (CNS) intravenous (IV) administration of CoA synthesis of the neurotransmitter ACh, responds to the availability of choline in results in a transient decrease in the heart but is also vital in several other bodily the blood and that the ability of neurons rate. These studies make it appear that processes. Choline is necessary: as a to make and release neurotransmitters, it is the adenosine portion of the CoA component of cell membranes, in cell including ACh, depends directly on the molecule which may be responsible for signaling molecules, in lipid metabolism concentration of amino acids and choline the decrease in heart rate rather than the and transportation, and as a major in the blood.17,18 pantethine, pantothenic acid, or cysteine source of methyl groups. Methylation Excellent research has been produced constituents of the molecule.24 reactions turn body processes on and by Marty Hinz, MD, and his groups over The accumulation of long chain off and activate and inactivate metabolic the recent decades substantiating that oral acyl fatty acid intermediates promotes intermediates.7 supplementation of amino acid precursors cardiac arrhythmias. This has been 74 BEST OF NATUROPATHIC MEDICINE TOWNSEND LETTER – FEB/MARCH 2013 Management