|
- <html>
- <head><title></title></head>
- <body>
- <h1></h1>
-
- <p></p>
- <p>
- <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.
- </p>
- <p>
- <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>
- <span><h3>REFERENCES</h3></span>
- <span>J Pathol. 2000 Aug;191(4):434-42. Expression of nitric oxide synthase isoforms and arginase in normal
- human skin and chronic venous leg ulcers. Abd-El-Aleem SA, Ferguson MW, Appleton I, Kairsingh S, Jude
- EB, Jones K, McCollum CN, Ireland GW.</span>
- <span>PLoS One. 2013;8(4):e57661. The occurrence of warfarin-related nephropathy and effects on renal and
- patient outcomes in korean patients. An JN, Ahn SY, Yoon CH, Youn TJ, Han MK, Kim S, Chin HJ, Na KY,
- Chae DW.</span>
- <span>Eur J Vasc Endovasc Surg. 2010 Jul;40(1):117-21. Oestradiol levels in varicose vein blood of patients
- with and without pelvic vein incompetence (PVI): diagnostic implications. Asciutto G, Mumme A, Asciutto
- KC, Geier B.</span>
- <span>Diabetes Care August 2003 vol. 26 no. 8 2482-2483. Fenofibrate Monotherapy Induced Rhabdomyolysis.
- Barker BJ, Goodenough RR, Falko JM.</span>
- <span>Endocrinology. 2011 Dec;152(12):4937-47. Aromatase deficiency confers paradoxical postischemic
- cardioprotection. Bell JR, Mellor KM, Wollermann AC, Ip WT, Reichelt ME, Meachem SJ, Simpson ER,
- Delbridge LM.</span>
- <span>J Pharmacol Exp Ther. 2004 Oct;311(1):109-14. Fenofibrate impairs rat mitochondrial function by
- inhibition of respiratory complex I. Brunmair B, Lest A, Staniek K, Gras F, Scharf N, Roden M, Nohl H,
- Waldhäusl W, Fürnsinn C.</span>
- <span>Am J Geriatr Cardiol. 2002;11(3). Primary Diastolic Heart Failure, Chatterjee K.</span>
- <span>Eur J Pharmacol. 1992 May 14;215(2-3):171-6. Chronic estrogen alters contractile responsiveness to
- angiotensin II and norepinephrine in female rat aorta. Cheng DY, Gruetter CA.</span>
- <span>Eur J Pharmacol. 2012 Aug 15;689(1-3):172-8. Frequency-dependent acceleration of cardiac
- repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic
- effects in female rabbits. Cheng J, Zhang J, Ma X, Su D.</span>
- <span>J Vasc Surg. 2000 Sep;32(3):544-9. High endogenous estradiol is associated with increased venous
- distensibility and clinical evidence of varicose veins in menopausal women. Ciardullo AV, Panico S,
- Bellati C, Rubba P, Rinaldi S, Iannuzzi A, Cioffi V, Iannuzzo G, Berrino F.</span>
- <span> Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):202-11. Antiarrhythmic and
- electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids. Dhein S, Michaelis B,
- Mohr FW. "All compounds exhibited a negative inotropic and chronotropic effect."</span>
- <span>Australas Med J. 2013 Mar 31;6(3):112-4. Life-threatening rhabdomyolysis following the interaction of
- two commonly prescribed medications. Fallah A, Deep M, Smallwood D, Hughes P.</span>
- <span>Curr Atheroscler Rep. 2009 Sep;11(5):343-9. Low-density lipoprotein in the setting of congestive heart
- failure: is lower really better? Horwich T.</span>
- <span>Am Heart J. 1952 Feb;43(2):215-27. Water and electrolyte content of cardiac and skeletal muscle in
- heart failure and myocardial infarction. ISERI LT, ALEXANDER LC, McCAUGHEY RS, BOYLE AJ, MYERS GB.</span
- >
- <span>Mol Cell Biochem. 2001 Oct;226(1-2):119-28. Concomitant accumulation of intracellular free calcium and
- arachidonic acid in the ischemic-reperfused rat heart. Ivanics T, Miklós Z, Dézsi L, Ikrényi K, Tóth A,
- Roemen TH, Van der Vusse GJ, Ligeti L.</span>
- <span>Circ Res. 1992 Jun;70(6):1180-90. Relation between glycolysis and calcium homeostasis in postischemic
- myocardium. Jeremy RW, Koretsune Y, Marban E, Becker LC.</span>
- <span> Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9886-90. Effects of long-chain polyunsaturated
- fatty acids on the contraction of neonatal rat cardiac myocytes. Kang JX, Leaf A.</span>
- <span> </span>
- <span>Angiology. 2009 Jun-Jul;60(3):283-9. Elevated serum estradiol/testosterone ratio in men with primary
- varicose veins compared with a healthy control group. Kendler M, Blendinger Ch, Haas E.</span>
- <span>Circ Heart Fail. 2013 Mar;6(2):287-92. Risk-benefit profile of warfarin versus aspirin in patients
- with heart failure and sinus rhythm: a meta-analysis. Lee M, Saver JL, Hong KS, Wu HC, Ovbiagele
- B.</span>
- <span>Can Med Assoc J. 1966 Jan 15;94(3):129-31. Cardiac myoglobin in myoglobinuria.</span>
- <span>Lewin PK, Moscarello MA.</span>
- <span>Lipids. 2011 Feb;46(2):163-70. Increasing DHA and EPA concentrations prolong action potential
- durations and reduce transient outward potassium currents in rat ventricular myocytes. Li HX, Wang RX,
- Li XR, Guo T, Wu Y, Guo SX, Sun LP, Yang ZY, Yang XJ, Jiang WP.</span>
- <span>J Appl Physiol. 1999 Nov;87(5):1909-13. Biphasic changes in heart performance with food restriction in
- rats. McKnight KA, Rupp H, Dhalla KS, Beamish RE, Dhalla NS.</span>
- <span>Eur J Pharmacol. 1998 Sep 4;356(2-3):261-70. The electrical and mechanical response of adult guinea
- pig and rat ventricular myocytes to omega3 polyunsaturated fatty acids. Macleod JC, Macknight AD,
- Rodrigo GC.</span>
- <span>Circulation: Heart Failure. 2012; 5: 493-503. Agonist-Induced Hypertrophy and Diastolic Dysfunction
- Are Associated With Selective Reduction in Glucose Oxidation. A Metabolic Contribution to Heart Failure
- With Normal Ejection Fraction. Mori J, Basu R, McLean BA, Das SK, Zhang L, Patel VB, Wagg CS, Kassiri Z,
- Lopaschuk GD, Oudit GY.</span>
- <span>Life Sci. 2001 Jan 12;68(8):881-8. Influence of estradiol and progesterone on the sensitivity of rat
- thoracic aorta to noradrenaline. Moura MJ, Marcondes FK.</span>
- <span>Toxicol Appl Pharmacol. 1998 Sep;152(1):99-106. Myopathy induced by HMG-CoA reductase inhibitors in
- rabbits: a pathological, electrophysiological, and biochemical study. Nakahara K, Kuriyama M, Sonoda Y,
- Yoshidome H, Nakagawa H, Fujiyama J, Higuchi I, Osame M.</span>
- <span>J Physiol. 2000 Mar 1;523 Pt 2:367-75. Inhibition of sarcoplasmic reticulum function by
- polyunsaturated fatty acids in intact, isolated myocytes from rat ventricular muscle.</span>
- <span>Negretti N, Perez MR, Walker D, O'Neill SC.</span>
- <span>Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of</span>
- <span>triiodothyronine in cardiac transplantation. Novitzky D</span>
- <span>Heart Rhythm. 2012 May;9(5):823-32. Estradiol promotes sudden cardiac death in transgenic long QT type
- 2 rabbits while progesterone is protective. Odening KE, Choi BR, Liu GX, Hartmann K, Ziv O, Chaves L,
- Schofield L, Centracchio J, Zehender M, Peng X, Brunner M, Koren G.</span>
- <span>J Vasc Surg. 2010 Apr;51(4):972-81. Estrogen receptor-mediated enhancement of venous relaxation in
- female rat: implications in sex-related differences in varicose veins. Raffetto JD, Qiao X, Beauregard
- KG, Khalil RA.</span>
- <span>Indian Pacing Electrophysiol. J. 2006;6(2):84-99.The Postural Tachycardia Syndrome (POTS):
- Pathophysiology, Diagnosis & Management. Raj SR</span>
- <span>Mol Cell Biochem. 1994 Mar 16;132(1):69-80. Modification of myosin isozymes and SR Ca(2+)-pump ATPase
- of the diabetic rat heart by lipid-lowering interventions. Rupp H, Elimban V, Dhalla NS.</span>
- <span>Biochem Biophys Res Commun. 1989 Oct 16;164(1):319-25. Diabetes-like action of intermittent fasting on
- sarcoplasmic reticulum Ca2+-pump ATPase and myosin isoenzymes can be prevented by sucrose. Rupp H,
- Elimban V, Dhalla NS.</span>
- <span>Biochem Biophys Res Commun. 1988 Oct 31;156(2):917-23. Sucrose feeding prevents changes in myosin
- isoenzymes and sarcoplasmic reticulum Ca2+-pump ATPase in pressure-loaded rat heart. Rupp H, Elimban V,
- Dhalla NS.</span>
- <span> Br J Pharmacol. 1995 Sep;116(2):1894-8. Effects of 3-hydroxy-3-methylglutaryl coenzyme A
- reductase inhibitors on mitochondrial respiration in ischaemic dog hearts.</span>
- <span>Satoh K, Yamato A, Nakai T, Hoshi K, Ichihara K.</span>
- <span> Eur J Pharmacol. 1994 Aug 3;270(4):365-9. Influence of 3-hydroxy-3-methylglutaryl coenzyme A
- reductase inhibitors on mitochondrial respiration in rat liver during ischemia. Satoh K, Nakai T,
- Ichihara K.</span>
- <span> </span>
- <span>Br J Pharmacol. 1997 Oct;122(4):772-8. Imbalance between the endothelial cell-derived contracting
- factors prostacyclin and angiotensin II and nitric oxide/cyclic GMP in human primary varicosis.
- Schuller-Petrovic S, Siedler S, Kern T, Meinhart J, Schmidt K, Brunner F.</span>
- <span>J Clin Invest. 1996 Nov 15;98(10):2244-50. Glucose plus insulin regulate fat oxidation by controlling
- the rate of fatty acid entry into the mitochondria. Sidossis LS, Stuart CA, Shulman GI, Lopaschuk GD,
- Wolfe RR.</span>
- <span>Orv Hetil. 2004 Feb 8;145(6):259-66. [New steroid hormone family: endogenous cardiac glycosides and
- their role in physiologic and pathologic conditions]. [Article in Hungarian] Somogyi J, Szalay J,
- Pándics T, Rosta K, Csermely P, Vér A.</span>
- <span>Headache. 2013 Jan;53(1):217-24. QT prolongation, Torsade de Pointes, myocardial ischemia from
- coronary vasospasm, and headache medications. Part 2: review of headache medications, drug-drug
- interactions, QTc prolongation, and other arrhythmias. Stillman MJ, Tepper DE, Tepper SJ, Cho L.</span>
- <span>Am J Physiol Cell Physiol. 2009 Apr;296(4):C766-82. Testosterone-augmented contractile responses to
- alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and
- NCX in the heart. Tsang S, Wong SS, Wu S, Kravtsov GM, Wong TM.</span>
- <span>Farmakol Toksikol. 1982 Jan-Feb;45(1):30-2. [Effect of digoxin, strophanthin and isolanid on oxygen
- absorption, oxidative phosphorylation and the amount of cytochromes in the myocardial mitochondria and
- their ATPase activity]. Tsyganiĭ AA, Medvinskaia NA, Rudenko AF.</span>
- <span>Eur Heart J. 1998 Jan;19(1):124-31. A non-invasive selective assessment of type I fibre mitochondrial
- function using 31P NMR spectroscopy. Evidence for impaired oxidative phosphorylation rate in
- skeletal muscle in patients with chronic heart failure. van der Ent M, Jeneson JA, Remme WJ, Berger R,
- Ciampricotti R, Visser F.</span>
- <span>Withering W. An account of the foxglove and some of its medical uses, with practical remarks on
- dropsy, and other diseases. In Willins FA, Keys TE, eds. Classics of Cardiology. Volume I. New York, NY:
- Henry Schuman, Dover Publications; 1941: 231–252.</span>
- <span>Eur J Clin Pharmacol. 2009 Dec;65(12):1169-74. Rhabdomyolysis associated with fibrate therapy: review
- of 76 published cases and a new case report. Wu J, Song Y, Li H, Chen J.</span>
- <span>Cardiovasc Res (2013) 97 (4): 676-685. Pressure-overload-induced heart failure induces a selective
- reduction in glucose oxidation at physiological afterload. Zhabyeyev P, Gandhi M, Mori J, Basu R.,
- Kassiri Z, Clanachan A., Lopaschuk GD, Oudit GY.</span>
- </p>
-
- © Ray Peat Ph.D. 2015. All Rights Reserved. www.RayPeat.com
- </body>
- </html>
|
