Magnesium and Potassium in Lone Atrial Fibrillation
Patrick Chambers, M.D. and VMAFer vagally mediated atrial
fibrillation
February, 2003
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.
Mg and Cell Membranes
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).
Mg and K
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.
Absorption and Excretion
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).
Hormones and Mg Homeostasis
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 and Mg
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).
Parathormone and Mg
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).
Vit D and Mg
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).
Cyclic AMP/cGMP and Taurine
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).
Autonomic Nervous System and Mg
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.
GERD
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.
MSG and Aspartate
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.
Idiopathic Postprandial State, Hypoglycemia and Impaired
Glucose Tolerance
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).
Hyperthyroidism
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
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).
Aldosterone and ANP
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).
Electrophysiology and Low Intracellular Mg/K
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.
Mg water and K loss
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.
References
1. Magnesium: We Don't Appear to be Getting Enough, Burton M.
Altura, Science News Online, August 29, 1998,
http://www.sciencenews.org/sn_arc98/8_29_98/food.htm
2. Be My Guest: Magnificent Magnesium
http://www.mksalaman.com/features/f1095/article2.html
3. Dietary Magnesium Affects Susceptibility of Lipoproteins
and Tissues to Peroxidation in Rats, Rayssiguier Y, Gueux E,
Bussiere L, Durlach J, Mazur A.. J Am Coll Nutr 1993 Apr 12(2)
133-7.
4. Importance of Potassium in Cardiovascular Disease, Sica et
al., J Clin Hypertens 4(3): 198-206, 2002.
5. Magnesium, Potassium and Hormones in Urines of Patients
with Essential Hypertension, Abstracts of Journal of Japanese
Society for Magnesium Research, J.J.S.Mg R. Vol. 14, No. 1
(1995), pp. 35-44.
http://www.mgwater.com/jmgr95_1.shtml#REP4
6. Oral Magnesium Supplementation to Patients Receiving
Diuretics: Normalization of Magnesium, Potassium and Sodium, and
Potassium Pumps in the Skeletal Muscles, Ugeskr Laeger (Denmark)
Jul 4 1994, 156 (27) p4007-10, 4013.
7. Daily Intake of Macro and Trace Elements in the Diet. 4.
Sodium, Potassium, Calcium, and Magnesium, Ann Ig (ITALY) Sep-Oct
1989, 1 (5) p923-42.
http://www.lef.org/prod_hp/abstracts/php-ab236a.html#57
8. Diagnosis of magnesium-induced diarrhoea, Fine, D.F. et al
(1991b) New England Journal of Medicine, 324, 1012-1017.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
9. Cytosolic Mg2+ Modulates Whole Cell K+ and Cl- Currents in
Cortical Thick Ascending Limb (TAL) Cells of Rabbit Kidney,
Kelepouris E, Kidney Int 37: 564, 1990
10. Mg(2+)-dependent inward rectification of ROMK1 channels
expressed in Xenopus oocytes, Nichols CG, Ho K, Hebert S, J
Physiol (Lond) 476: 399-409, 1994
http://barttersite.org/hypomagnesemia.htm
11. Body Composition, Health Status, and Urinary Magnesium
Excretion Among Elderly People, Lowik, M.R. et al (1993)
Magnesium Research 6, 223-232.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
12. Magnesium in Clinical Practice, Jean Durlach, Section I,
Elements of Magnesium Biology, pp 1-39, John Libbey &
Company, 1985.
http://www.mgwater.com/durex01.shtml
13. Magnesium Deficiency Produces Insulin Resistance and
Increased Thromboxane Synthesis, Hypertension (USA), 1993, 21/6
II (1024-1029).
http://www.ionicminerals.com/research/magnesium/arts.html
14. Disorders of Magnesium Metabolism, JIFCC, v 11 (2), 1999,
pp 10-18.
http://www.ifcc.org/ejifcc/vol11no2/pdf/Magnesium_Article.pdf
15. Magnesium metabolism, a review, Ebel, H. and Gunther. T.
(1980), Journal of Clinical Chemistry and Clinical Biochemistry,
18, 257-270.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
16. The Relationship Between Dietary Intake and Urinary
Excretion of Sodium, Potassium, Calcium and Magnesium: Belgian
Interuniversity Research on Nutrition and Health. Kesteloot, H.
and Joossens, J.V. (1990), J. Hum. Hyperts. 4, 527-533.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
17. Magnesium and carbohydrate metabolism, Therapie (France),
1994, 49/1 (1-7)
http://www.ionicminerals.com/research/magnesium/arts.html
18. Hypertension, Diabetes Mellitus, and Insulin Resistance:
the Role of Intracellular Magnesium, Paolisso G, et al. Am J
Hypertens 1997 Mar 10(3): 368-370 .
http://www.spectracell.com/diabetesmellius.html
19. Cell Magnesium Transport and Homeostasis: Role of
Intracellular Compartments, Romani et al (1993),
Miner.Electrolyte Metab. 19, 282-289.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
20. The Role of Magnesium in Clinical Biochemistry: An
Overview, Ryan, M.F. (1991), Am. Clin. Biochem. 28, 19-26.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
21. Magnesium Metabolism and Deficiency, Rude, R.K. (1993)
Endocrinol. Metabol. Cli North Am. 22, 377-395.
http://www.foodstandards.gov.uk/multimedia/pdfs/evm-01-13.pdf
22. Magnesium and carbohydrate metabolism, Therapie (France),
1994, 49/1
http://www.ionicminerals.com/research/magnesium/arts.html
23. Magnesium and Glucose Homeostasis, Diabetologia (Germany,
Federal Republic of), 1990, 33/9 (511- 514)
http://www.ionicminerals.com/research/magnesium/arts.html
24. Magnesium and the Cardiovascular System: I. New
Experimental Data on Magnesium and Lipoproteins, Durlach et al.,
Chapter 113, in Molecular Biology of Atherosclerosis, © John
Libbey & Company Ltd, pp. 507-512
http://www.mgwater.com/dur24.shtml
25. Renal Hypomagnesemia in Human Diabetes Mellitus: Its
Relation to Glucose Homeostasis, McNair P, Christensen MS,
Christiansen C, et al: Eur J Clin Invest 1982; 12:81-85.
26. Subclinical hyperthyroidism as a risk factor for atrial
fibrillation, Auer J, Scheibner P, Mische T, Langsteger W, Eber
O, Eber B. Am Heart J 2001;142:838-42.
http://www.tsh.org/research/new/utiger1/1
27. Thyrotoxic Periodic Paralysis: An Overview, Rev Neurol
1999 Sep 16-30; 29(6): 510-2.
http://www.periodicparalysis.org/PPRC/PP/
28. Combining Structural Genomics and Enzymology: Completing
the Picture in Metabolic Pathways and Enzyme Active Sites, Heidi
Erlandsen et al., Current Opinion in Structural Biology 2000,
10:719-730.
29. Catechol-O-Methyl Transferase Activity: Assay,
Distribution and Pharmacological Modification, Ilkka
Reenilä, Institute of Biomedicine, Department of
Pharmacology and Toxicology, University of Helsinki, Finland,
1999.
http://ethesis.helsinki.fi/julkaisut/laa/biola/vk/reenila/catechol.pdf
30. The Medical Biochemistry Page, Copyright © 1996-2002
Dr. Michael W. King
http://www.indstate.edu/thcme/mwking/aminoacidderivatives.html
31. The Role and Mechanisms of Angiotensin II in Regulating
the Natriuretic Peptide Gene Expression in Response to Cardiac
Overload, 2.4. Natriuretic Peptides, Maria Suo, April 2002, Oulu
University Library
http://herkules.oulu.fi/isbn9514266994/html/x1344.html
32. Magnesium and the Cardiovascular System: I. New
Experimental Data on Magnesium and Lipoproteins, Durlach et al.,
Chapter 113, in Molecular Biology of Atherosclerosis, © John
Libbey& Company Ltd, pp. 507-512
http://www.mgwater.com/dur24.shtml
33. Cardiovascular Consequences of Magnesium Deficiency and
Loss: Pathogenesis, Prevalence and Manifestations. Magnesium and
Chloride Loss In Refractory Potassium Repletion, Mildred S.
Seelig, M.D., M.P.H., American Journal of Cardiology 63:4G-21G,
1989.
http://www.mgwater.com/cardio.shtml
34. Magnesium, Clin. Sci. 57:121, 1979
http://www.mdschoice.com/elements/elements/major_minerals/magnesium.htm
35. Cardiovascular Med. 3:637, 1978
http://www.mdschoice.com/elements/elements/major_minerals/magnesium.htm
36. Relationship of Juxtaglomerular Apparatus and Adrenal
Cortex to Biochemical and Extracellular Fluid Volume Changes in
Magnesium Deficiency, Cantin M, Lab Invest 22:558-568,
1970.
http://www.mgwater.com/conseq.shtml
37. Plasma Magnesium Concentration as a Possible Factor in the
Control of Aldosterone Secretion, Care AD, McDonald IR, Biochem J
87:2P-3P, 1963.
http://www.barttersite.com/consequences_of_magnesium_defici.htm
38. Consequences of Magnesium Deficiency on the Enhancement of
Stress Reactions; Preventive and Therapeutic Implications (A
Review), Mildred S. Seelig, MD, Journal of the American College
of Nutrition, Vol. 13, No. 5, 429-446 (1994).
http://www.coralcalmag.com/stress.htm
39 Effects of Prolonged Strenuous Exercise on Plasma Levels of
Atrial Natriuretic Peptide and Brain Natriuretic Peptide in
Healthy Men, Haruo Ohba, MD et al., Am Heart J 141(5): 751-758,
2001.
http://www.medscape.com/viewarticle/409229
40. Eplerenone: A New Aldosterone Receptor Antagonist - Are
the FDA's Restrictions Appropriate?, Domenic A. Sica, MD, J Clin
Hypertens 4(6):441-445, 2002.
http://www.medscape.com/viewarticle/445177
41.
https://secure.salu.net/cgi-perl/get.cgi?pub=50136&ext=doc
42. New Insights Into the Role of Aldosterone in Cardiorenal
Disease and the Clinical Implications Symposium held in Anaheim,
California on November 10, 2001, Copyright © 2002 the
University of Michigan Medical School.
http://www.medscape.com/viewprogram/1004
43. The Biochemical Basis of Neuropharmacology, Cooper, J.R.,
Bloom, F.E., and Roth, R.H. (1996) Seventh Edition, Oxford
University Press.
http://artsci-ccwin.concordia.ca/psychology/psyc358/Lectures/transmit2.htm
44. Excitotoxins, Blaylock, R. Santa Fe: Health Press,
1997.
http://smart-drugs.net/ias-excitotoxins.htm
45. Excitatory Amino Acids as a Final Common Pathway for
Neurologic Disorders, Lipton, S. & Rosenberg, P., (1994) "
NEJM 330: 613-22.
http://smart-drugs.net/ias-excitotoxins.htm
46. Inhibition of Astrocyte Glutamate Uptake by Reactive
Oxygen Species: Role of Antioxidant Enzymes, Sorg, 0. et al
(1997), Mol. Med 7: 431-40.
http://smart-drugs.net/ias-excitotoxins.htm
47. http://www.msgtruth.org/diabetes.htm
48. Magnesium Deficiency Produces Insulin Resistance and
Increased Thromboxane Synthesis, Hypertension (USA), 1993, 21/6
II (1024-1029).
http://www.ionicminerals.com/research/magnesium/arts.html
49. Functional Hypoparathyroidism and Parathyroid Hormone and
Organ Resistance in Human Magnesium Deficiency, Rude RK, Oldham
SB, Singer FR, Clin Endocrinol (Oxf) 5: 209-224, 1976.
http://www.barttersite.com/mgburn.htm
50. Acid Peptic Disorders, Ronald Hsu, MD, FACP, FACG Director
of Endoscopy, Division of Gastroenterology, University of
California Davis Medical Center.
http://216.239.53.100/search?q=cache:pqa7PN_AWQwC:medocs.ucdavis.edu/IMD/420B/esylabus/acidpeptic.htm
51. Hypomagnesemia, The Bartter Site
http://www.barttersite.com/hypomagnesemia.htm
52. Magnesium and Potassium-Sparing Diuretics, Ryan MP,
Magnesium 1986;5(5-6):282-92.
http://www.barttersite.com/mgK.htm
53. Magnesium in Clinical Practice, Jean Durlach, Section V, ,
Magnesium and Therapeutics, pp. Pages 219-228, John Libbey &
Company, 1985.
http://www.mgwater.com/durex03.shtml#x1.321
54. An Increase in Plasma Atrial Natriuretic Peptide
Concentration During Exercise Predicts a Successful Cardioversion
and Maintenance of Sinus Rhythm in Patients with Chronic Atrial
Fibrillation, Wozakowska-Kaplon, B, et al., Pacing Clin
Electrophysiol, Vol. 23 (Pt 2), November 2000, pp. 1876-79.
55. Metabolic Alkalosis, Sameer Yaseen, MD, August 2,
2002.
http://www.emedicine.com/med/topic1459.htm
56. Hypomagnesemia, Zalman S. Agus, Journal of the American
Society of Nephrology, Vol 10 (7), July, 1999.
http://www.barttersite.com/hypomagnesemia_Agus.htm
57. Magnesium: Its Proven and Potential Clinical Significance,
Fox et al., South Med J 94(12):1195-1201, 2001.
www.medscape.com/viewarticle/423568
58. Magnesium status and health, Dreosti, I.E. (1995),
Nutrition reviews53, S23-S27.
http://www.mgwater.com/dur06.shtml
59. Grass Tetany, Chapter 19, Magnesium and neuro-muscular
transmission, André Voisin.
http://www.soilandhealth.org/01aglibrary/010106voisin/010106gtchap19.html
60. Magnesium in Clinical Practice, Jean Durlach, Section V,
Magnesium and Therapeutics, pp. Pages 219-228, John Libbey &
Company, 1985.
http://www.mgwater.com/durex03.shtml#x1.321
61. Consequences of Magnesium Deficiency on the Enhancement of
Stress Reactions; Preventive and Therapeutic Implications (A
Review), Seelig MS, J Am Coll Nutr, 1994 Oct, 13:5, 429-46.
http://www.mgwater.com/conseq.shtml
62. Magnesium-Deficient Myocardium Demonstrates an Increased
Susceptibility to an In Vivo Oxidative Stress, Freedman AM,
Cassidy MM, Weglicki WB: Magnes Res 4:185-189, 1991.
http://www.mgwater.com/dur11.shtml
63. Magnesium and lipids in cardiovascular disease,
Rayssiguier, Y. & Gueux, E. (1986), J. Am. Coll. Nutr. 5,
507-519.
http://www.mgwater.com/dur24.shtml
64. Magnesium and Lipid Metabolism. In Metal Ions in
Biological Systems, Magnesium and Its Role in Biology, Nutrition
and Physiology, Rayssiguier, Y. (1990), ed. H. Sigel, Vol. 26,
pp. 341-358. New York: Marcel Dekker.
http://www.mgwater.com/dur11.shtml
65. Endocrine Physiology Lecture 5, Aldosterone by Dale
Buchanan Hales, PhD, Department of Physiology &
Biophysics.
http://www.uic.edu/classes/phyb/phyb402dbh/lecture5.ppt
66. Effect of Exercise in the Heat on Plasma Renin and
Aldosterone with Either Water or a K Rich Electrolyte Solution,
Francis, K.T. & MacGregor, R. (1978): Aviation Space Environ.
Med. 49, 461-465.
http://www.mgwater.com/dur18.shtml
67. New Experimental and Clinical Data on the Relationship
between Magnesium and Sport, Y. Rayssiguier, C. Y. Guezennec, and
J. Durlach, Magnesium Research (1990) 3, 2, 93-102.
http://www.mgwater.com/dur18.shtml
68. Effects of Right Lateral Decubitus Position on Plasma
Norepinephrine and Plasma Atrial Natriuretic Peptide Levels in
Patients with Chronic Congestive Heart Failure, Miyamoto, S, et
al., American Journal of Cardiology, Vol. 89, January 15, 2002,
pp. 240-42.
69. An Increase In Plasma Atrial Natriuretic Peptide
Concentration during Exercise Predicts a Successful Cardioversion
and Maintenance of Sinus Rhythm in Patients with Chronic Atrial
Fibrillation, Wozakowska-Kaplon, B, et al., Pacing Clin
Electrophysiol, Vol. 23 (Pt 2), November 2000, pp. 1876-79
70. Cyclic GMP-Mediated Inhibition of L-type Ca2+ Channel
Activity by Human Natriuretic Peptide in Rabbit Heart Cells,
Tohse N, et al., British Journal of Pharmacology, Vol. 114, No.
5, March 1995, pp. 1076-82.
http://herkules.oulu.fi/isbn9514252721/html/x549.html
72 Lone Atrial Fibrillation: Towards A Cure, Larsen, HR.,
2003, pp. 96, 63.
73 Principles and Applications of Bioelectric and Biomagnetic
Fields by Jaakko Malmivio and Robert Plonsey, Chapter 24, Cardiac
Defibrillation in Bioelectromagnetism, Oxford University Press,
1995
http://butler.cc.tut.fi/~malmivuo/bem/bembook/24/24.htm
74. Guidelines for the Management of Patients with Atrial
Fibrillation, Fuster et al., ACC/AHA/ESC J Am Coll Cardiol
2001;38:1266i-1xx
http://www.acc.org/clinical/guidelines/atrial_fib/V_pathophysiological.htm
75. Atrial Fibrillation: From Cell to Bedside, Phillip Sager,
MD, Cochairs: Robert Myerburg, MD, and Jasmir Sra, MD, Autonomic
Aspects of Atrial Fibrillation by Philip T. Sager, MD,
http://www.medscape.com/viewarticle/422901
76. Update on Atrial Fibrillation, EMEX Workshop, Friday 29
September 2000 Amsterdam Electrophysiology of Atrial
Fibrillation, Prof. Arthur Wilde, MD Dept. of Clinical
Electrophysiology, University Hospital, Amsterdam
http://www.emex.nl/3_uoaf_ab2.html
77. Molecular Adaptations in Human Atrial Fibrillation:
Mechanisms of Protein Remodeling, by Bianca Johanna Josephina
Maria Brundel, p. 15.
http://www.ub.rug.nl/eldoc/dis/medicine/b.j.j.m.brundel/c1.pdf
78. Non-pharmacological Treatment of Atrial Fibrillation, by
Ole-Gunnar Anfinsen, MD, PhD, Indian Pacing and Electrophysiology
Journal, 2002, 2:4.
http://www.ipej.org/0201/anfinsen.htm
79. Apex-to-base dispersion of refractoriness underlies the
proarrhythmic effect of hypokalaemia/hypomagnesaemia in the
rabbit heart, J Electrocardiol 2002 Jul;35(3):245-52.
http://www.uic.edu/classes/pcol/pcol425/restricted/Vogel/arr.pdf
80. Dispersion of Cell-To-Cell Uncoupling Precedes Low
K+-Induced Ventricular Fibrillation, N. Tribulova, M. Manoach, D.
Varon, L. Okruhlicova, T. Zinman, A. Shainberg, Physiol. Res. 50:
247-259, 2001.
http://www.biomed.cas.cz/physiolres/2001/issue3/tribul.htm
81. Magnesium Potassium Interactions in Cardiac Arrhythmia.
Examples of Ionic Medicine. Magnes Trace Elem (Switzerland) 92
1991, 10 (2-4) p193-204.
http://www.lef.org/prod_hp/abstracts/potassiumabs.html#27
82. OGTT: Indications and Limitations, by Roger Nelson, MD,
Mayo Clin Proc 63:263-269, 1988.
83. Tietz' Fundamentals of Clinical Chemistry (5th ed.) c.
2001
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