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<strong>Heart and hormones </strong> The heart's unique behavior has given cardiologists a
particularly mechanical perspective on biology. If a cardiologist and an oncologist have anything to talk
about, it's likely to be about why cancer treatments cause heart failure; a cardiologist and an
endocrinologist might share an interest in "cardioprotective estrogen" and "cardiotoxic obesity." Cell
physiology and bioenergetics aren't likely to be their common interest. Each specialty has its close
involvement with the pharmaceutical industry, shaping its thinking.
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<span> The drug industry has been lowering the numbers for cholesterol, blood pressure, and
blood glucose that are considered to be the upper limit of normal, increasing the number of customers
for their prescription drugs. Recently, publications have been claiming that the upper limit of the
normal range of heart rates should be lower than 100 beats per minute; this would encourage doctors to
prescribe more drugs to slow hearts, but the way the evidence is being presented, invoking the
discredited "wear and tear" theory of aging, could have many unexpected harmful consequences. It would
reinforce existing misconceptions about heart functions. </span>
<span> A few decades ago, diuretics to lower blood pressure and digitalis/digoxin to increase
the heart's strength of contraction were the main treatments for heart disease. In 1968, the annual
number of deaths in the US from congestive heart failure (in which the heart beats more weakly, pumping
less blood) was 10,000. By 1993 the number had increased to 42,000 per year. More recently, the annual
number of deaths in which heart failure is the primary cause was more than 55,000. During these decades,
many new drugs for treating heart disease were introduced, and the use of digoxin has decreased
slightly. People with heart failure usually live with the condition for several years; at present about
5.7 million people in the US live with heart failure. The prevalence of, and mortality from, other
cardiovascular diseases (such as hypertension and abnormalities of the coronary arteries) are higher,
but congestive heart failure is especially important to understand, because it involves defective
function of the heart muscle itself.</span>
<span> Although Albert Szent-Gyorgyi is known mostly for his discovery of vitamin C and
his contribution to understanding the tricarboxylic acid or Krebs cycle, his main interest was in
understanding the nature of life itself, and he focused mainly on muscle contraction and cancer growth
regulation. In one of his experiments, he compared the effects of estrogen and progesterone on rabbit
hearts. A basic property of the heart muscle is that when it beats more frequently, it beats more
strongly. This is called the staircase effect, from the way a tracing of its motion rises, beat by beat,
as the rate of stimulation is increased. This is a logical way to behave, but sometimes it fails to
occur: In shock, and in heart failure, the pulse rate increases, without increasing the volume of blood
pumped in each contraction.</span>
<span> Szent-Gyorgyi found that estrogen treatment decreased the staircase effect, while
progesterone treatment increased the staircase. He described the staircase as a situation in which
function (the rate of contraction) builds structure (the size of the contraction). Progesterone allowed
"structure" to be built by the contraction, and estrogen prevented that.</span>
<span>(It's interesting to compare these effects of the hormones to the more general idea of anabolic and
catabolic hormones, in which more permanent structures in cells are affected.)</span>
<span> The rapid and extensive alternation of contraction and relaxation made possible by
progesterone is also produced by testosterone (Tsang, et al., 2009). Things that increase the force of
contraction are called inotropic, and the things that promote relaxation are called lusitropic;
progesterone and testosterone are both positively inotropic and lusitropic, improving contraction and
relaxation. Estrogen is a negative lusitropic hormone (Filice, et al., 2011), and also a negative
inotropic hormone (Sitzler, et al., 1996), that is, it impairs both relaxation and
contraction. </span>
<span> Another standard term describing heart function is chronotropy, referring to the
frequency of contraction. Because of the staircase interaction of frequency and force, there has been
some confusion in classifying drugs according to chronotropism. In a state of shock or estrogen
dominance, an inotropic drug will slow the heart rate by increasing the amount of blood pumped. This
relationship caused digitalis' effect to be thought of as primarily slowing the rate of contraction
(Willins and Keys, 1941), though its main effect is positively inotropic. It was traditionally used to
treat edema, by stimulating diuresis, which is largely the result of its inotropic action. Progesterone
and testosterone's inotropic action can also slow the heart beat by strengthening it.</span>
<span> I think it was a little before Szent-Gyorgyi's heart experiment that Hans Selye had
discovered that a large dose of estrogen created a shock-like state. Shock and stress cause estrogen to
increase, and decrease progesterone and testosterone.</span>
<span> About 30 years after Szent-Gyorgyi's work, people began to realize that digoxin and other
heart stimulating molecules can be found in animals and humans, as metabolites of progesterone and
possibly DHEA (Somogyi, et al., 2004). </span>
<span> The regulatory proteins that are involved in estrogen's negative lusi- and inotropic
actions (decreasing pumping action) have been known for over 20 years to be regulated by the thyroid
hormone to produce positive lusi- and inotropic actions on the heart (increasing its pumping action),
and thyroid's beneficial effects on heart and skeletal muscle have been known empirically for 100 years.
However, drug centered cardiologists, reviewing the currently available drugs approved by the FDA, have
typically concluded that "drugs targeted to achieve these objectives are not available" (Chatterjee,
2002).</span>
<span> When a muscle or nerve is fatigued, it swells, retaining water. When the swelling
is extreme, its ability to contract is limited. Excess water content resembles a partly excited state,
in which increased amounts of sodium and calcium are free in the cytoplasm. Energy is needed to
eliminate the sodium and calcium, or to bind calcium, allowing the cell to extrude excess water and
return to the resting state. Thyroid hormone allows cells' mitochondria to efficiently produce energy,
and it also regulates the synthesis of the proteins (phospholamban and calcisequestrin) that control the
binding of calcium. When the cell is energized, by the mitochondria working with thyroid, oxygen, and
sugar, these proteins rapidly change their form, binding calcium and removing it from the contractile
system, allowing the cell to relax, to be fully prepared for the next contraction. If the calcium isn't
fully and quickly bound, the cell retains extra water and sodium, and isn't able to fully relax.</span>
<span> Heart failure is described as "diastolic failure" when the muscle isn't able to fully
relax. In an early stage, this is just a waterlogged (Iseri, et al., 1952), fatigued condition, but when
continued, the metabolic changes lead to fibrosis and even to calcification of the heart muscle.</span>
<span> Many children approaching puberty, as estrogen is increasing and interfering with thyroid
function, have "growing pains," in which muscles become tense and sore after prolonged activity. When
hypothyroidism is severe, it can cause myopathy, in which the painful swollen condition involves the
leakage of muscle proteins (especially myoglobin) into the blood stream, allowing it to be diagnosed by
a blood test. The combination of hypothyroidism with fatigue and stress can lead to the breakdown and
death of muscle cells, rhabdomyolysis. </span>
<span> The blood lipid lowering drugs, statins and fibrates, impair mitochondrial respiration
(Satoh, et al., 1995, 1994; Brunmair, et al., 2004), and increase the incidence of rhabdomyolysis
(Barker, et al., 2003; Wu, et al., 2009; Fallah, et al., 2013). Interference with coenzyme Q10 is not
the only mechanism by which they can cause myopathy (Nakahara, et al., 1998). The harmful effect of
lowering cholesterol seems to be relevant to heart failure: "In light of the association between high
cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains
controversial (Horwich, 2009).</span>
<span> Heart muscle and skeletal muscle are similar in their structural responses to
interference with mitochondrial functions, namely, swelling, reduced contractile ability, and
dissolution. When myoglobin has been found in the blood and urine, it has been assumed to come from
skeletal muscles, but the heart's myoglobin has been found to be depleted in a patient with
myoglobinuria (Lewin and Moscarello, 1966). When heart failure is known to exist, similar changes can be
found in the skeletal muscles (van der Ent, et al., 1998).</span>
<span> Stress, in the form of pressure-overload (Zhabyeyev, et al., 2013), or overactivity of
the renin-angiotensin system (Mori, et al., 2013) and sympathetic nervous system or adrenergic chemicals
(Mori, et al., 2012), or a failure of energy caused by diabetes, insulin deficiency, or hypothyroidism,
causes a shift of energy production from the oxidation of glucose to the oxidation of fatty acids, with
the release, rather than oxidation, of the lactic acid produced from glucose. This sequence, from
reduced efficiency of energy production to heart failure, can be opposed by agents that reduce the
availability of fatty acids and promote the oxidation of glucose. Niacinamide inhibits the release of
free fatty acids from the tissues, and thyroid sustains the oxidation of glucose. This principle is now
widely recognized, and the FDA has approved a drug that inhibits the oxidation of fatty acids
(raloxazine, 2006), but which has serious side effects. Glucose oxidation apparently is necessary for
preventing the intracellular accumulation of free calcium and fatty acids (Jeremy, et al., 1992; Burton,
et al., 1986; Ivanics, et al., 2001). The calcium binding protein which is activated by thyroid and
inhibited by estrogen seems to be activated by glucose and inhibited by fatty acids (Zarain-Herzberg and
Rupp, 1999). </span>
<span> Diabetes or fasting increases free fatty acids, and forces cells to shift from oxidation
of glucose to oxidation of fatty acids, inhibiting the binding of calcium (McKnight, et al., 1999).
Providing a small amount of sugar (0.8% sucrose in their drinking water) restored the calcium binding
and heart function, without increasing either thyroid hormone or insulin (Rupp, et al., 1988, 1999,
1994). Serum glucose was lowered, as the ability to oxidize sugar was restored by lowering free fatty
acids. Activity of the sympathetic nervous system is lowered as efficiency is increased. </span>
<span> Digoxin stimulates mitochondrial energy production in skeletal and heart muscle
(Tsyganil, et al., 1982), increasing the oxidation of glucose, rather than fatty acids, supporting the
effect of thyroid hormone. The statins have the opposite effect, decreasing the oxidation of
glucose. </span>
<span> One of estrogen's effects is to chronically increase the circulation of free fatty acids,
and to favor the long chain polyunsaturated fatty acids, such as EPA and DHA. These fatty acids, which
slow the heart rate (Kang and Leaf, 1994), extend the excited state (action potential: Li, et al.,
2011), and are negatively inotropic (Dhein, et al., 2005; Macleod, et al., 1998; Negretti, et al.,
2000), are being proposed as heart protective drugs. (EPA and alpha-linoleic acid also prolong the QT
interval: Dhein, et al., 2005). </span>
<span> Many publications still promote estrogen as a cardioprotective drug, but there is now
increased recognition of its role in heart failure and sudden cardiac death. A prolonged excited state
(action potential) and delayed relaxation (QT interval) are known to increase the risk of arrhythmia and
sudden death, and estrogen, which causes those changes in humans, causes sudden cardiac death in
susceptible rabbits, with an adrenergic stimulant increasing the arrhythmias, and progesterone and
androgen preventing them (Odening et al., 2012). Progesterone's protective effect seems to be the result
of accelerating recovery of the resting state (Cheng, et al., 2012). </span>
<span> Estrogen's interactions with adrenalin in promoting blood vessel constriction has been
known for many years (for example, Cheng and Gruetter, 1992). Progesterone blocks that effect of
estrogen (Moura and Marcondes, 2001). Environmental estrogens such as BPA can exacerbate ventricular
arrhythmia caused by estrogen (Yan, et al., 2013). The hearts of mice genetically engineered to lack
aromatase, the enzyme that synthesizes estrogen, were more resistant to damage by being deprived of
blood for 25 minutes (Bell, et al., 2011), leading the authors to suggest that aromatase inhibition
might be helpful for heart disease. </span>
<span> In the stressed, energy depleted failing heart, muscle cells die and are replaced by
connective tissue cells. The growth produced by over-exposure to adrenergic stimulation leads to
stiffening and reduced functioning. However, under the influence of thyroid hormone a high work load
leads to functional enlargement, which simply increases the pumping ability. Because of the traditional
belief that heart cells can't replicate, this functional growth was believed to be produced purely by
the enlargement of cells, but in recent years the existence of stem cells able to create new heart
muscle has been recognized. Thyroid is likely to be one of the hormones responsible for allowing stem
cells to differentiate into cardiomyocytes.</span>
<span> In this context, of cellular differentiation as a life-long process, we can see the
changes of a failing heart as a differentiation which is forced to take an inappropriate course. The
calcification of blood vessels caused by phosphate excess and vitamin K deficiency involves the
expression of a protein which has its proper place in the skeleton. The replacement of heart muscle by
fibrous connective tissue and even bone is a basic biological problem of differentiation, and the
responsible factors--stress, increased estrogen, deficient thyroid hormone, suppression of glucose
oxidation by fatty acids, etc.--are involved in the problems of differentiation that occur in other
degenerative processes, such as sarcopenia, dementia, and cancer.</span>
<span> There have been arguments about the nature of wound healing and regeneration, regarding
the origin of the new cells--whether they are from the dedifferentiation of local cells, or the
migration of stem cells. The evidence is that both can occur, depending on the tissue and the situation.
The deterioration of an organ is probably not a question of a lack of stem cells, but of changed
conditions causing them to differentiate into something inappropriate for the full functioning of that
organ. </span>
<span> Various stresses can cause cells to dedifferentiate, but hypoxia is probably a common
denominator. In the absence of estrogen, hypoxia can activate the "estrogen receptor." Estrogen is
in some situations a hormone of dedifferentiation, facilitating the formation of new cells in stressed
tissues, as aromatase is induced. However, the presence of polyunsaturated fats, tending to increase in
concentration with age, causes the processes of renewal to produce exaggerated inflammation, with
prostaglandins participating in the processes of development and differentiation. Estrogen, by
increasing the concentration of free fatty acids, especially polyunsaturated fatty acids, contributes to
the metabolic shift away from glucose oxidation, toward the formation of lactic acid, and away from the
full organ-specific differentiation.</span>
<span> This perspective puts heart failure, cancer, and the other degenerative diseases onto the
same biological basis, and shows why certain conditions and therapies can be appropriate for all of
them.</span>
<span> Problems that seem relatively trivial become more meaningful when they are seen in terms
of these mechanisms. Some problems that become very common by middle age are "palpitations," orthostatic
hypotension, orthostatic tachycardia, and varicose veins. The negative inotropic effect of estrogen in
the heart has a parallel in the smooth muscle of veins, in which the muscles are weakened, and their
distensibility increased, when estrogen isn't sufficiently opposed by progesterone. This allows the
veins in the lower part of the body to be distended abnormally when standing, reducing the amount of
blood returning to the heart, so that the volume pumped with each stroke is small, requiring faster
beating. The reduced blood volume reaching the brain can cause fainting. When it becomes chronic, it can
lead to the progressive distortion of the veins. An excess of estrogen is associated with varicose veins
in men, as well as women. (Raj, 2006; Ciardullo, et al., 2000; Kendler, et al., 2009; Asciutto, et al.,
2010; Raffetto, et al., 2010).</span>
<span> The simplicity of things such as supplementing thyroid, progesterone, and sugar, avoiding
an excess of phosphate in relation to calcium, and avoiding polyunsaturated fats, makes it possible for
people to take action themselves, without having to depend on the medical system. Most physicians still
warn their patients of the dangers of thyroid supplements, especially the active T3 hormone, for their
heart, but in at least one specialty, its value is recognized. Heart transplant surgeons have discovered
that administering T3 to the brain-dead heart donor before removing the heart improves its viability and
function in the recipient (Novitzky, 1996). Around this time, the manufacturers of Cytomel conceived the
idea of marketing it as a "heart drug," which would make it much more profitable.</span>
<span> Another technique that is easy to use to lower blood pressure and improve heart rhythm is
to breathe into a paper bag for a minute or two at a time, to increase the carbon dioxide content of the
blood. This has a vasodilating effect, reducing the force required to circulate the blood, and reduces
anxiety. Rhubarb and emodin (a chemical found in rhubarb and cascara) have been found to have heart
protective actions. A considerable amount of research showed that vitamin K is effective for treating
hypertension, but again, most doctors warn against its use, because of its reputation as a clot forming
vitamin. Recently, the value of the "blood thinner" warfarin, a vitamin K antagonist, has been
questioned for people with heart failure (An, et al., 2013; Lee, et al., 2013). There have been several
recent warnings about the production of arrhythmia by drugs that increase serotonin's effects (e.g.,
Stillman, et al., 2013).</span>
<span> Measuring the speed of relaxation of the Achilles tendon reflex twitch is a
traditional method for judging thyroid function, because in hypothyroidism the relaxation is visibly
delayed. This same retardation can be seen in the electrocardiogram, as a prolonged QT interval, which
is associated with arrhythmia and sudden death. Insomnia, mania, and asthma are other conditions in
which defective relaxation is seen, under the influence of low thyroid function, and an insufficiently
opposed influence of estrogen.</span>
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