Lone Atrial Fibrilation (LAF) is AF without discernible cardiovascular disease, e.g., without congestive heart failure, high blood pressure, prior cardiac surgery, rheumatic heart disease, etc. It has been associated with a number of diseases primarily involving organs other than the heart. These include seemingly widely disparate disorders such as hyperthyroidism, gastroesophageal reflux disease (GERD), dysautonomia (abnormality of autonomic nervous system), impaired glucose tolerance, etc. The term "defective substrate" has become integral to any discussion of the cause of LAF. Organ candidates for this "substrate" include at the top of the list the heart, as well as kidney, adrenal gland, gastrointestinal tract and autonomic nervous system. This defect could involve an enzyme, a hormone or receptor site, a membrane pump, channel or exchanger, to name a few. It could be environmental, genetic or both. Magnesium (Mg) deficiency has emerged as a significant player in the etiology of LAF. This is not completely unexpected, since some 350 different enzymes(1) or about 80% of all enzymatic reactions in the body(2) rely on magnesium. Although much has been written on the role of Mg deficiency in other diseases, little has been devoted to LAF.
One of the most important roles of Mg involves maintenance of the intracellular environment. It does this primarily by attaching to phospholipids in membranes (both of the cell wall and cell organelles) to reduce their permeability and enhance polarizing electrostatic effects(12). It also a required cofactor in the various membrane ATP (energy requiring) pumps. The most important of these pumps is the Na/K pump. Others include Ca/Mg, K/H and Na/H pumps. In addition there are channels (such as Ca and Na) and exchangers (such as Na-Mg, Na-Ca and Na-H). Neither channels nor exchangers require ATP and are passive (rely on diffusion). Some of these are also adversely affected by Mg deficiency. Mg is a Ca channel blocker and Mg deficiency leads to increased intracellular Ca via channel (and pump) due to a Ca gradient of 25,000:1 (outside v inside)(9). Mg deficiency also results in dysfunction of the Na-Mg exchanger(56), leading to increased intracellular Na via exchanger (and pump) due to a Na gradient of 13:1(71). If there is insufficient Mg for adequate ATP, then the primarily extracellular cations sodium (Na) and calcium (Ca) tend to leak into the cells and the primarily intracellular cations potassium (K) and Mg tend to leak out. However, membrane leakiness in magnesium deficiency depends less on ATP related activity and more on the membrane stabilizing effects of magnesium phospholipd complexes(12). This leakiness disrupts cellular function and proper gradients (difference between intracellular and extracellular concentrations). In addition Mg is an antioxidant and Mg deficiency allows accelerated free radical damage to cell membranes (lipid peroxidation), further compromising cellular cation (positive ion) homeostasis(3,24,32,60,61). Maintenance of proper cationic (Na, K, Ca, Mg) gradients is especially critical for successful muscle contraction and nerve impulse transmission. In fact the earliest symptoms of magnesium deficiency are neuromuscular symptoms, e.g., muscle twitching, difficulty sleeping, difficulty swallowing. Accordingly, the list of disorders associated with Mg deficiency is top heavy with neuromuscular diseases, e.g., asthma (bronchial smooth muscle), migraines and eclampsia (vascular smooth muscle), cramps (skeletal muscle), LAF (cardiac muscle) and even chronic constipation (GI smooth muscle).
Like Mg, K inhibits free radical formation(4). In fact, there are a number of parallels between these two cations. Both are inextricably linked to specific anions (Na for K and Ca for Mg). Hyperkalemia (like hypermagnesemia) does not typically occur in patients with normal renal function. Aldosterone increases the secretion/excretion of both K and Mg(5). Successfully replenishing a K deficiency (like a Mg deficiency) in the presence of low intracellular Mg is difficult and takes months(6). Even in the presence of a normal serum K, reduced dietary K can be problematic, just as for Mg(4). K and Mg both can reduce high blood pressure(7). Fruits and vegetables are great sources for both minerals (mother was right). Both because K is so vital to cardiac function and because Mg is so vital to K utilization(33), any discussion of Mg and LAF is incomplete without inclusion of K.
In addition to passive diffusion there appears to be an ATP requiring mechanism for Mg absorption from the GI tract(8). Similarly, in the kidney in addition to passive diffusion there appears to be an additional active transport system for the reabsorption of Mg(9,10,12,19). In short, Mg via ATP is required for a portion of its own GI absorption and renal reabsorption(19). Likewise GI absorption of K is decreased and urinary excretion increased, if there is a Mg (and therefore ATP) shortage in GI and kidney cells respectively(14,19,56). Both absorption and reabsorption of K (and Mg) worsen with age(11).
Neither Mg nor K has good neurohormonal controls for either GI absorption or renal reabsorption to maintain proper balance (v parathormone, calcitonin and Vitamin D for Ca, aldosterone and atrial natriuretic peptide (ANP) for Na)(35). However, insulin, parathormone (PTH) and Vitamin D do play a role in Mg homeostasis by increasing cellular uptake(13). The former is primarily associated with carbohydrates and the latter two with Ca, a Mg antagonist. A variety of other hormones has been implicated in urinary magnesium wasting. These include catecholamines, TSH, T3, T4 (thyroxine) and calcitonin (thyroid), glucocorticoids (affect glucose metabolism, especially cortisol) and mineralicorticoids (affect sodium metabolism, especially aldosterone), glucagon (pancreas), antidiuretic hormone (ADH from pituitary) and angiotensins (liver and lungs)(14,15,20,57). Catecholamines are produced by both the adrenal medulla (humoral) and sympathetic nerves (neurotransmitter). Corticoids (corticosteroids) are produced by the adrenal cortex. High dietary sodium and calcium may also result in urinary magnesium wasting(16).
Insulin causes cellular uptake of Mg(12). Magnesium deficiency results in insulin resistance(13) as well as impaired insulin secretion(17,22,23). Furthermore, the most significant mechanism for urinary magnesium wasting is probably through glycosuria (glucose in the urine) secondary to impaired glucose tolerance(14,21,23,25). Insulin resistance appears to be due to defective tyrosine-kinase activity (requires Mg) at the insulin receptor level and increased intracellular calcium(18). This resistance mandates release of more insulin, causing more Mg (and K) to be transported from blood into cells. Intracellular Mg (and K) must then be maintained against a greater concentration gradient (defective Ca/Mg ATPase and Na/K ATPase pumps). The concomitant urinary Mg wasting aggravates further this with additional membrane instability (decreased magnesium phospholipid complexes), causing more Mg loss and more insulin resistance (see cAMP/cGMP discussion below).
The parathyroid gland in response to low serum magnesium or calcium releases PTH. PTH then increases GI absorption and renal reabsorption of Mg(12). However, adequate magnesium is required for parathyroid hormone synthesis and secretion(20). So this also is a kind of a hormonal catch 22 (Mg is required for the efficacy of one of its regulating hormones) similar to the electrolyte catch 22 (Mg is required for its own cellular uptake). Mg deficiency also causes end organ PTH resistance (serum Ca does not rise when PTH is increased in Mg deficient patients)(12,48,55).
Intestinal absorption of magnesium and calcium is enhanced by Vitamin D(52). Mg absorption in Vitamin D deficiency is decreased(72). In addition serum concentration of 1,25 dihydroxy cholecalciferol (cholecalciferol = Vitamin D3) is low or low/normal and does not rise in response to a low calcium diet. This is because the formation of 1,25 dihydroxy cholecalciferol involves a magnesium dependent hydroxylase enzyme(12). Magnesium deficiency also results in end organ resistance to vitamin D and its metabolites(12). This is another hormonal catch 22. Vitamin D increases net absorption of Mg but to a lesser degree than for Ca (34,35). The subsequently elevated blood Ca may result in greater urinary Mg wasting(12).
Insulin and catecholamines function via receptors on target cell membranes, which involve cyclic AMP (cAMP). On the other hand, cholinergic receptor activity (PNS) involves cyclic GMP (cGMP). Adenylate cyclase (for cAMP production) requires Mg, whereas guanylate cyclase (for cGMP production) requires Ca(13). Consequently, in Mg deficiency the intracellular cAMP/cGMP ratio, normally between 10 and 100 to 1, is reversed(52). This partially explains the insulin receptor resistance (low cAMP) seen in impaired glucose tolerance associated with Mg deficiency. cGMP mediates the effects of ANP in target cells, i.e., enhanced natriuresis(31). This may be another reason why VMAF episodes (enhanced cholinergic receptor activity) and LAF episodes due to Mg deficiency, both associated with high cGMP, seem to revert to NSR more spontaneously. Interestingly, hyperinsulinism tends to maintain this reduction in cAMP(13). Only when intracellular GTP is raised do these neurohormones (mainly insulin and catecholamines) stimulate adenylate cyclase(13). Jean Durlach, M.D., Editor-in-Chief, Magnesium Research, President of the International Society for the Development of Research on Magnesium, and author of Magnesium in Clinical Practice, suggests that taurine may effect this turnaround (less cGMP and more cAMP). Catecholamines and insulin favor cellular influx of taurine. Taurine is a powerful membrane stabilizer. It also chelates Ca, a Mg antagonist, facilitates maintenance of intracellular K and opposes the undesirable cellular effects of insulin and catecholamines(13). Taurine plays an important role in Mg deficiency. MSG (monosodium glutamate) can lead to taurine deficiency. Taurine is made from cysteine and glutamate competes with cysteine for uptake(46).
Mg is required for activity by the cholinesterase enzymes(13). One of these, acetyl cholinesterase degrades acetylcholine, the neurotransmitter substance for the PNS and for the first part of the sympathetic nervous system (SNS), specifically the nicotinic receptors of the SNS. In fact, deficiency of magnesium and excess calcium both increase the release of acetylcholine. Deficiency of either magnesium or calcium prolongs the effect of acetylcholine(58). Mg deficiency translates to enhanced vagal tone further augmented by too much or too little Ca.
Catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO) catabolize (breakdown) catecholamines. MAO catabolizes neurotransmitter catecholamines (at nerve endings), while COMT is more active in catabolizing circulating catecholamines(30). Both are part of the sympathetic nervous system (SNS). COMT requires Mg as a cofactor(28,29), i.e., low Mg translates to slightly higher sympathetic tone. These enzymatic shortfalls might produce an exaggerated response of either the PNS or the SNS at transition points, a time when many LAF episodes arise, e.g., just after ending a sprint or lying down. The neurotransmitter substance or hormone secreted on each occasion is not degraded, resulting in a prolonged overresponse. COMT also breaks down dopamine, an important hormone produced during sexual activity. Sexual activity triggers some episodes for many afibbers. The dopamine no doubt triggers automaticity in an aberrant focus with a resulting increase in PACs (see EP discussion below). The overresponding vagus causes a shortening of the AERP. Mg deficiency in this scenario (independent of K) may be the sole cause of bedtime episodes and even some more typically adrenergic episodes.
The "alkaline tide" precedes the start of any meal. This is caused by gastric cell secretion of H and Cl into the lumen for digestion of food and simultaneous extrusion of K and HCO3 into the blood. The resulting alkalosis (increased blood pH due to HCO3) causes bicarbonaturia (HCO3 in urine) to lower this pH. Unfortunately, K is lossed in the urine (kaliuria) with HCO3(54). This causes a transient drop in blood K. Furthermore, there is evidence that high vagal tone may sustain basal gastric acid hypersecretion in some persons and temporary hypersecretion during stress in others(49). Some cases of GERD (gastroesophageal reflux disease) and nonulcer dyspepsia (NUD) probably result in transient hypokalemia via the constant steady alkaline state (in plasma) that accompanies the slightly hyperacidic state (in the stomach). The K/H pump also rectifies this increase in blood pH. H goes into the blood and K comes into the cells. This requires cardiac muscle cells to maintain their intracellular K concentration against a greater gradient. Normally the concentration of K within heart muscle cells is 150 millimoles/liter (v. four mm/l outside the cell), a considerable gradient (almost 40:1) to maintain(9). Ingested protein stimulates more HCl secretion (and a stronger alkaline tide and greater kaliuria). Other suggested mechanisms for GERD related episodes of LAF include stimulation via irritation of the nearby vagus nerve during episodes of reflux. Some VMAFers (vagally mediated atrial fibrillation) associate their episodes with GERD. Curiously, many of them prefer to sleep on their right side. Vagal tone is increased when lying in the right lateral decubitus position (lying on one's right side)(67). This is because the heart is slightly higher (v. the left side position) relative to the carotid baroreceptor. This pressure receptor in the neck senses more hydrostatic pressure and signals the vagus nerve to increase tone (bad for a VMAFer). However, the preference may be because and this position promotes gastric emptying and possible relief for a GERDer.
Monosodium glutamate (MSG) is a common trigger of AF (and PACs) for many LAFers. NMDA (N-Methyl-D-Aspartate) receptors are located on neurons and are associated with the Ca channel(42). When glutamate or aspartate attaches to the NMDA receptor, it triggers a flow of sodium (Na) and calcium (Ca) ions into the neuron, and an outflow of potassium (K), firing the neuron. ATP pumps are required to return the ions and restore the resting state. The Ca channel is blocked by magnesium. This helps maintain membrane potentials near resting value. If the repolarized resting state cannot be maintained, e.g., hypoglycemia, defective pump (as in Mg deficiency), then the neuron fires and the channels open. This pump failure gradually allows excessive calcium/sodium build up inside the cell, which will eventually kill it(43,44). Furthermore, ATP pumps are required not only to return the ions but also to remove the glutamate. Glutamate is then converted into glutamine, another process that requires ATP. That is a total of three separate ATP and Mg requiring steps. Free radicals hinder this(45). Mg has a circadian excretory rhythm, with maximal excretion occurring at night(56). This compounds the picture for VMAFers, whose episodes are often triggered at night, since Mg deficiency is both vagotonic and glutamate potentiating. For these reasons, MSG and even mild GERD make dinner out a risky proposition for many LAFers.
In idiopathic postprandial syndrome (formerly called reactive hypoglycemia) there is an overresponse of insulin to a simple carbohydrate load. However, there is no yo-yo effect or reflexive overresponse by glucagon and catecholamines. Such individuals usually have a normal OGTT (oral glucose tolerance test) and can only be diagnosed by a low postprandial blood glucose simultaneous with symptoms (sweating, weakness, hunger, anxiety,? LAF) simultaneously(82,83).
Those with with impaired glucose metabolism hyperrespond with insulin to a carbohydrate meal. The ensuing hypoglycemia stimulates release of glucagon (pancreas) and catecholamines with consequent hyperglycemia (yo-yo effect)(72). Catecholamines and glucagon stimulate gluconeogenesis (release of glucose from cells that store glycogen), most notably from the liver. Syndrome X (or Metabolic Syndrome = includes high blood pressure, obesity, diabetes, high blood insulin and triglyceride levels) represents the far end of the spectrum of this disorder of carbohydrate metabolism. First a serum hemoglobin A1C (measures the average blood glucose levels over the preceding three months) or fasting blood glucose and then an OGTT are the best tests to diagnose diabetes. Mg deficiency plays an important role in this process (see insulin section above).
Magnesium deficiency also causes release of catecholamines(12). They stimulate release of fatty acids that complex with blood Mg, further aggravating the Mg shortfall(60,62,63). Insulin and catecholamines both cause intracellular migration of K and decrease serum K(12). Consequently, catecholamines (and insulin) cause a greater K (and Mg) gradient, promoting steady loss of cardiac muscle cell K (and Mg). This is in addition to the direct impact of Mg on insulin (see above).
Hypomagnesemia is a common problem in hyperthyroid patients. T3/T4 (T4 = thyroxine) cause urinary Mg wasting(13). Thyroid hormones also induce shifting of magnesium into the cells. This Mg deficiency also leads to low intracellular K (defective Na/K ATPase pump and unstable membrane), as evidenced by the fact that 14% of hyperthyroids have AF(26) and 10% have hypokalemic periodic paralysis(27).
Dehydration (via the renin angiotensin aldosterone system (RAAS)) stimulates release of aldosterone to reabsorb Na and with it water. In exchange, K is secreted/excreted, thereby lowering serum K. Aldosterone receptors are also present in colon and skin. In the distal colon, aldosterone enhances active Na absorption and K (and Mg) excretion/secretion (via pump and channel)(50). Exercise induced dehydration stimulates aldosterone release, causing increased loss of K and Mg in sweat(65,66). Excessive exercise also stimulates secretion of ADH, catecholamines, TSH, cortisol and aldosterone, all of which cause urinary Mg wasting(57) (see above).
Mention aldosterone and most think renal Na reabsorption and renal K secretion/excretion. Few realize that aldosterone also causes urinary Mg wasting due to blood volume expansion and consequent greater delivery of sodium, calcium, and magnesium to the distal renal tubules(14). Magnesium deficiency enhances angiotensin-induced aldosterone synthesis (RAAS)(47). Indeed, there have been many articles written touting the antihypertensive qualities of Mg supplementation in those deficient. Magnesium deficiency causes hypertrophy of the juxtaglomerular apparatus (JGA), located in the kidney(36,37). This releases renin, which ultimately increases aldosterone, lowering serum K (and Mg). This, of course, again aggravates the extracellular/intracellular K (and Mg) gradient and membrane permeability.
Aldosterone levels fluctuate diurnally-highest concentration being at 8 AM, lowest at 11 PM, in parallel to cortisol and ACTH rhythms(64). These levels increase with age. Aldosterone is a major contributor to LAF, predominantly via the resultant increase in the intracellular Na/K ratio. Unfortunately, the deleterious effects of aldosterone and the RAAS do not end with Na/K. Recent research(41) has shown that the heart and endothelium both contain receptors for aldosterone and that this mineralicorticoid is responsible for left ventricular fibrosis, dilatation, and hypertrophy. Spironolactone, a K sparing diuretic, blocks many of the adverse effects of aldosterone but has some adverse side effects, including causing the development of breasts in males and irregular menses in females. An exciting new diuretic called eplerenone(39) is similarly K sparing and cardioprotective, but without the side effects of spironolactone. Evidence has accumulated in recent years indicating that these K sparing drugs may also exert some Mg-sparing properties(51,52,59).
ANP is the hormonal counterpart to aldosterone. It causes renal reabsorption of K and excretion/secretion of Na. Congestive heart failure (CHF) and atrial fibrillation (AF) stimulate release of ANP from atrial cells via atrial muscle cell stretching that occurs at such times. ANP is also secreted during exercise(68). In fact, hypoxia is a potent stimulus for ANP(70). K and ATP (and Mg) mediate the release of ANP. Many believe that ANP is helpful in terminating episodes of AF by favorably rebalancing the intracellular Na/K ratio. It is also a known Ca channel blocker(69).
Muscle cells (skeletal, smooth and cardiac) contract during depolarization (excitation phase) and relax during repolarization. During a portion of the relaxation phase, the cell is refractory to further stimulation (refractory period)(75). AF requires a shortened atrial effective refractory period (AERP), enhanced atrial dispersion, slow conduction velocity and a trigger (increased PACs)(78). Dispersion of refractoriness is nothing more than a measure of how much variability in AERP exists between atrial muscle cells. Greater variability in AERP from cell to cell implies greater dispersion. The mechanism of AF is based on the now proven Moe wavelet theory (1959)(74), which requires both reentry and automaticity. Reentry occurs when the advancing wavefront of depolarization encounters refractory tissue in such a way that it reenters its own path, creating a wavelet (circular wave). The lack of AERP uniformity between cells can force some unusual paths of conduction (colorfully called circus movements), making creation of these wavelets or closed circuits a real possibility. Wavelets are described by the equation: wavelength = (conduction velocity) x (AERP)(75,76). Atrial conduction velocity (via His Purkinje system) is about 1m/s and AERP<50 ms results in AF 80% of the time. Therefore, a microreentrant wavelet is something around or less than 5 mm in circumference(73). In addition to reentry, there must be automaticity, whereby a single atrial focus fires repeatedly (PACs). The number of PACs is inversely proportional to intracellular K and Mg and directly proportional to intracellular Ca(80,81). The SA and AV nodes and the rest of the His Purkinje conduction system have innate pacemaking properties (automaticity). Catecholamines can cause automaticity in cells not so disposed (foci of ectopics)(76). Since PACs arise outside the normal conduction system of the heart, the impulse travels via an alternate less efficient pathway with slower conduction velocity. This further contributes to shortening of the wavelength and dispersion of refractoriness (see above equation). These simultaneously occurring conditions (PACs, slow velocity, shortened AERP and enhanced dispersion) lead to AF by fragmentation of the propagating wavefront of depolarization. Multiple reentrant wavelets (six wavelets or involvement of about 75% of atrial tissue constitute critical mass for sustaining AF)(73,76) are created. The dispersion of refractoriness allows the wavelets to meander around the atrium forming a moving barrier against any successful wave of contraction. Instead, additional wavelets are created. Hence, there is no P wave, unlike atrial flutter. Autonomic tone (especially vagal but also sympathetic) can shorten AERP and increase atrial dispersion. Hypokalemia and hypomagnesemia can also increase atrial dispersion(79). Inhomogeneous distribution of vagal nerve endings will increase dispersion of refractoriness(77). Atrial dispersion is also a function of atrial electrical remodeling (increased intracellular Ca)(76). Electrical remodeling causes loss of physiologic rate adaptation, i.e., the AERP fails to adapt to the heart rate, especially during bradycardia(74), when it should lengthen. There is also structural remodeling (increase in atrial size) as well as ultrastructural or contractile remodeling (76,77). When the conduction velocity increases, the wavelets begin to disappear or fuse because the advancing waveletfront of depolarization catches up to its trailing tail of refractory tissue. The wavelets are forced to enlarge or coalesce, but then they are more likely to bump into others, canceling themselves. At some point their numbers dip below critical mass and AF is terminated. Increasing sympathetic tone causes an increase in conduction velocity (dromotropism) (74). This latter is instrumental in terminating VMAF episodes.
To address the growing problem of inadequate Mg intake, several Mg rich drinking waters have appeared on the market. These are mineral waters or their approximations. They include Unique Water (Australia), Noah's California Spring Water (110 mg Mg/liter) and Waller Water (developed by Erling Waller and containing up to 1500 mg of Mg/liter). All (and they are not alone) have pHs well over 8 and have the potential to cause urinary K wasting, due to bicarbonaturia (see GERD discussion above). However, a generous squeeze from a fresh lemon addresses nicely not only this concern but also adds a touch of taste. Hexahydrated Mg is otherwise especially beneficial, because it provides more bioavailable Mg. This results in not only enhanced GI absorption but also more biologically active ionized Mg. If the concentrations of ionized magnesium falls 25 to 40 percent below normal-irrespective of the total amount of magnesium present-magnesium-dependent enzymes no longer function properly(1). There are also some Mg preparations that dissolve in water (Natural Calm with magnesium citrate). However, oral Mg supplementation in tablet form enjoys considerable popularity and success. Herbert Mansmann, M.D., Director of the Magnesium Reasearch Laboratory at Thomas Jefferson Medical College, has developed an effective magnesium dosing regimen that exploits nighttime absorption(40). However, whichever route one chooses, the maximum tolerated dose (MTD) should be approached carefully. Once exceeded, the K and Mg loss in loose stool is regressive and may easily trigger a breakthrough episode of LAF. Many factors help or hinder Mg absorption and directly impact the efficacy of oral supplementation.
Finally, heart rate variability (HRV) has always been an independent prognosticator of longevity. Greater vagal tone translates to longer life, all else being equal. Perhaps the "defective substrate" of VMAF is nothing more than the combination of many years of poor diet, skipped meals and poor hydration along with excessive exercise in individuals already possessing a slow heart rate. But it's never too late to change. Increased dietary Mg and regular moderate exercise with plenty of hydration will increase ANP(38,53), the antialdosterone hormone, thus flushing out excess Na and keeping RAAS at bay.
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