What to do about multinodular goiter

[messtafarian]

The way I came to the research of Dr. Peat was through an instant Google PhD in Thyroid Problems, as I appear to have one. His name and Thyroid sort of go together in the search engines and I started to sort of home in over the past couple weeks. My diagnosis is Toxic Multinodular Goiter -- meaning I have multiple cysts inside my thyroid, one of which is very hot and is bringing my TSH down to .26; which is just slightly lower than "normal" ranges, although I wonder sometimes given my weight problems and my general Largeness ( 5'10", 185), not to mention my severe history of female issues if that TSH number really reflects the state of my thyroid at all; it could be my pituitary gland, for all I know.

In any case, since I'm fibrotic in multiple organs the advice of Dr. Peat seems to more often than not involve optimizing thyroid output. I am actually convinced I need *more* thyroid hormone regardless of my TSH output. I also need progesterone right now, even though the advice is to "fix the thyroid first."

The problem is I am not sure exactly what to do about "fixing the thyroid." I will not be offered thyroid medication by the endocrinologist because she will state, logically, that I am already subclinically hyperthyroid and do not need to supplement with hormones. I will be offered radiation to kill the offending hot nodule, resulting in lifelong hypothyroidism, or I will be offered a thyroidectomy or lobectomy to get rid of the thing altogether.

My game plan for now is to do nothing medically for the goiter and try to get the rest of my organ systems running as optimally as I can. However RP has said in several places that one should "fix the thyroid" -- in my case, fixing it would essentially mean killing it from the conventional medical standpoint; and I will not really legally be able to self-medicate with thyroid supplementation; either T4 or Cytomel. In my case the fear would be that this would bring on a "thyroid storm."

What would you do if you were me; or is there any guidance from RP on this specific condition that I've missed?

 

[j.]

Maybe this is kind of a delicate problem. Have you considered paying RP for a nutritional consultation? I think he charges $75. A lot of people just e-mail him, but for something like this, maybe there'll need to be a back and forth.

I'm guessing though that he'll advise thyroid supplementation. I'm not sure the way he advises is dangerous. He advises usually no more than 5 mcg in an hour, because that's what the thyroid produces.

 

[messtafarian]

of course I would pay Dr. Peat for his advice on this matter, lol. How do I do that? I know some people do email him but you're right, this is possibly a bit more involved than some other questions.

 

[j.]

of course I would pay Dr. Peat for his advice on this matter, lol. How do I do that? I know some people do email him but you're right, this is possibly a bit more involved than some other questions.

Google contact ray peat, and one of the links will take you to a form where you can ask for a consultation. Paying him though seems harder than buying things online. Anyway, the information is on that webpage.

 

[messtafarian]

Okay, I just contacted him and requested a consultation. I'll let you all know how it goes :)

 

[charlie]

Okay, I just contacted him and requested a consultation. I'll let you all know how it goes :)

Please let us know what he says! It could help a lot of future people here.

 

[messtafarian]

Hi All:

This is RP's first reply to me regarding this. Very helpful; and very helpful articles included: several talk about the necessity of good thyroid function and supplementation and heart disease -- others talk about the helpful nature of progesterone in the therapy of hypertension.

When I asked him about this I told him about my goiter; he responded to the issue of heart problems since; I think, if I treat it appropriately then using progesterone and thyroid supplementation then it can only be therapeutic:




Did they describe the nature of the goiter's "toxicity"? Do you have any signs of hyperthyroidism, such as increased basal temperature and resting heart rate, increased oxygen consumption, requirements for calories and water, or changes in reflexes? It used to be widely recognized that menorrhagia is closely associated with hypothyroidism, and the associated over-exposure to estrogen promotes the growth of fibroids. Some of the articles below describe the effects of hypothyroidism on the circulatory system. T3 is needed for relaxation of the heart and blood vessels.

Another approach to correcting blood pressure is with diet. Vitamin K, for example, is needed to prevent calcification of the blood vessels, so its function is more basic than the "calcium blockers'".




Expert Rev Cardiovasc Ther. 2010 Nov;8(11):1559-65.
Hypothyroidism and hypertension.
Stabouli S, Papakatsika S, Kotsis V.
Pediatric Intensive Care Unit, Hippokration Hospital, Thessaloniki, Greece.
Hypothyroidism has been recognized as a cause of secondary hypertension. Previous
studies on the prevalence of hypertension in subjects with hypothyroidism have
demonstrated elevated blood pressure values. Increased peripheral vascular
resistance and low cardiac output has been suggested to be the possible link
between hypothyroidism and diastolic hypertension. The hypothyroid population is
characterized by significant volume changes, initiating a volume-dependent, low
plasma renin activity mechanism of blood pressure elevation. This article
summarizes previous studies on the impact of hypothyroidism on blood pressure and
early atherosclerotic process.

Endocrine. 2004 Jun;24(1):1-13.
Hypothyroidism as a risk factor for cardiovascular disease.
Biondi B, Klein I.
Department of Clinical and Molecular Endocrinology and Oncology, University of
Naples Federico II School of Medicine, Via S. Pansini 5, 80131, Naples, Italy.
The cardiovascular risk in patients with hypothyroidism is related to an
increased risk of functional cardiovascular abnormalities and to an increased
risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar
in subclinical and overt hypothyroidism, suggesting that a lesser degree of
thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid
patients, even those with subclinical hypothyroidism, have impaired endothelial
function, normal/depressed systolic function, left ventricular diastolic
dysfunction at rest, and systolic and diastolic dysfunction on effort, which may
result in poor physical exercise capacity. There is also a tendency to increase
diastolic blood pressure as a result of increased systemic vascular resistance.
All these abnormalities regress with L-T4 replacement therapy. An increased risk
for atherosclerosis is supported by autopsy and epidemiological studies in
patients with thyroid hormone deficiency. The "traditional" risk factors are
hypertension in conjunction with an atherogenic lipid profile; the latter is more
often observed in patients with TSH >10 mU/L. More recently, C-reactive protein,
homocysteine, increased arterial stiffness, endothelial dysfunction, and altered
coagulation parameters have been recognized as risk factors for atherosclerosis
in patients with thyroid hormone deficiency. This constellation of reversible
cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that
the benefits of treatment of mild thyroid failure with appropriate doses of
L-thyroxine outweigh the risk.

J Clin Endocrinol Metab. 2004 Jul;89(7):3455-61.
Thyroid function and blood pressure homeostasis in euthyroid subjects.
Gumieniak O, Perlstein TS, Hopkins PN, Brown NJ, Murphey LJ, Jeunemaitre X,
Hollenberg NK, Williams GH.
Endocrinology, Diabetes and Hypertension Division, Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2,
Boston, MA 02115, USA.
Overt and subclinical hypothyroidism are associated with increased systemic
vascular resistance and hypertension. We examined the relationship between
thyroid function and blood pressure homeostasis in euthyroid individuals. A total
of 284 subjects (68% hypertensive) consumed high- (200 mmol) and low- (10 mmol)
sodium diets, and their blood pressure responses were assessed as percentage
change in the mean arterial pressure (MAP). p-Aminohippuric acid clearance was
used to estimate effective renal plasma flow. Renal vascular resistance (RVR) was
calculated as MAP divided by effective renal plasma flow. Serum free T(4) index
(FTI) was lower (P < 0.0001) and TSH was higher (P = 0.046) in hypertensive
compared with normotensive subjects independent of other baseline
characteristics. FTI (beta = -1.51, P < 0.0001), baseline MAP, and race
independently predicted MAP salt sensitivity. The FTI relationship with salt
sensitivity adjusted for baseline MAP and race was similar among normotensive
(beta = -1.42, P = 0.008) and hypertensive subjects (beta = -1.66, P = 0.0001).
FTI correlated negatively with high- (P = 0.0001) and low- (P = 0.008) salt RVR,
whereas TSH correlated positively with high- (P = 0.016) and low- (P = 0.012)
salt RVR independent of age, gender, race, and body mass index. We have found
that FTI is lower and TSH is higher in hypertensive compared with normotensive
euthyroid subjects and that FTI independently predicts blood pressure salt
sensitivity. These data show that the influence of thyroid function on blood
pressure homeostasis extends into euthyroid range and likely reflects the action
of thyroid hormone on peripheral vasculature.

Am Heart J. 2002 Apr;143(4):718-24.
Effects of thyroid replacement therapy on arterial blood pressure in patients
with hypertension and hypothyroidism.
Dernellis J, Panaretou M.
Department of Cardiology, Vostanion Hospital, Mytilini, Greece.
BACKGROUND: Hypothyroidism is frequently accompanied by cardiac dysfunction,
increased vascular resistance, and a greater prevalence of hypertension.
Treatment of hypothyroidism may lead to normalization of blood pressure, although
some patients may exhibit sustained hypertension. The mechanism of this condition
may be the alterations in aortic stiffness.
METHODS: Aortic stiffness was studied in 30 patients who never received treatment
for hypertension or hypothyroidism, 15 patients with normal blood pressure and
hypothyroidism, and 15 patients with hypertension and normal thyroid function.
Thirty healthy age- and sex-matched subjects with normal thyroid function served
as control subjects. Aortic diameter evaluated by M-mode echocardiography and
blood pressure measured by a sphygmomanometer were used to calculate aortic
stiffness index.
RESULTS: Patients with high blood pressure and hypothyroidism, those with normal
blood pressure and hypothyroidism, and those with hypertension and normal thyroid
function showed increased aortic stiffness index (18.8 +/- 6.4, 11.7 +/- 3.5, and
19.2 +/- 5.3 vs 9.5 +/- 2.7; P <.001) compared with control subjects. In 15
patients with hypertension and hypothyroidism, levothyroxine therapy showed only
a small decrease in blood pressure (151/105 +/- 9/9 mm Hg, group A). The
remaining 15 patients showed complete normalization of blood pressure (118/83 +/-
8/3 mm Hg, group B). Aortic stiffness index was increased in group A compared
with group B both before and after treatment (before, 24.0 +/- 4.1 vs 13.7 +/-
3.2; and after, 22.3 +/- 4.2 vs 11.1 +/- 2.9; P <.001 for both comparisons).
Felodipine was given to patients in group A after levothyroxine was administered,
resulting in normalization of blood pressure and a significant decrease of aortic
stiffness index (P <.001). Aortic stiffness index was decreased in patients with
hypothyroidism and hypertension after administration of levothyroxine (9.5 +/-
2.2; P <.001) and felodipine (14.5 +/- 7.5; P <.001) therapy, respectively.
Percent changes in systolic blood pressure showed a significant correlation with
percent changes in aortic stiffness index in all patients (r = 0.65, P <.001).
After multivariate adjustment, aortic stiffness index (odds ratio = 1.9932;
confidence interval = 1.1481 to 3.4605) was significantly associated with
incomplete normalization of blood pressure.
CONCLUSIONS: Patients with hypertension and hypothyroidism have increased aortic stiffness. Aortic stiffness is decreased in all patients, whereas hypertension is
completely reversible in 50% of patients by hormone replacement therapy.
Sustained hypertension may be due to increased aortic stiffness.

Endocrinol Metab Clin North Am. 1994 Jun;23(2):379-86.
Hypertension in thyroid disorders.
Saito I, Saruta T.
Health Center, Keio University, Tokyo, Japan.
Hypertension is more common in hypothyroidic patients than in euthyroid controls
in older age groups. Treatment of the thyroid deficiency alone lowers blood
pressure in most patients. Hemodynamically, cardiac output is reduced and total
peripheral resistance is elevated. The latter probably is secondary to an
increase of sympathetic nervous tone and a relative increase in alpha-adrenergic
response. In hyperthyroidism, elevation of diastolic blood pressure is uncommon.
Systolic hypertension is more common in younger age groups. Treatment of the
hyperthyroidism alone lowers systolic blood pressure in most patients. An
increase in cardiac output and a decrease in total peripheral resistance
accompany the hyperthyroidism. Potentiation of catecholamine action by an excess
of thyroid hormone has been invoked as an explanation, because thyroid hormone
excess is accompanied by increased beta-adrenergic receptors in some tissue,
including heart.

Med Ann Dist Columbia. 1970 Feb;39(2):78-81 passim.
Hypertension and myxedema. Case report and a review of the literature.
Ronan JA Jr, Weintraub AM.

Hypertension. 2003 Mar;41(3):598-603.
Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone.
Fukuyama K, Ichiki T, Takeda K, Tokunou T, Iino N, Masuda S, Ishibashi M,
Egashira K, Shimokawa H, Hirano K, Kanaide H, Takeshita A.
Department of Cardiovascular Medicine, Kyushu University Graduate School of
Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
Thyroid hormone has a broad effect on cardiovascular system.
3,3',5-triiodo-l-thyronine (T3), a biologically active form of thyroid hormone,
increases cardiac contractility. T3 causes arterial relaxation and reduction of
systemic vascular resistance, resulting in an increase in cardiac output.
However, the molecular mechanisms of vascular relaxation by T3 are incompletely
characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1
receptor (AT1R) expression in vascular smooth muscle cells. T3 dose-dependently
decreased expression levels of AT1R mRNA, with a peak at 6 hours of stimulation.
Binding assay using [125I]Sar1-Ile8-Ang II revealed that AT1R number was
decreased by stimulation with T3 without changing the affinity to Ang II. T3
reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT1R
promoter activity measured by luciferase assay was reduced by 50% after 9 hours
of T3 administration. mRNA stability was also decreased by T3. Real-time
quantitative reverse transcription-polymerase chain reaction and Western blot
analysis revealed that AT1R mRNA and protein were downregulated in the aorta of
T3-treated rats. These results suggest that T3 downregulates AT1R expression both
at transcriptional and posttranscriptional levels, and attenuates biological
function of Ang II. Our results suggest that downregulation of AT1R gene
expression may play an important role for T3-induced vascular relaxation.

Internist (Berl). 2010 May;51(5):603-4, 606-8, 610.
[Thyroid diseases and hypertension].
[Article in German]
Spitzweg C, Reincke M.
Medizinische Klinik und Poliklinik II, Campus Grosshadern, Klinikum der
Universität München, Ludwig-Maximilians-Universität München, Marchioninistrasse
15, 81377, München, Deutschland. [email protected]
Thyroid hormones have several well-recognized effects on the vasculature and
heart, resulting in characteristic cardiovascular changes in thyroid disease,
including an increase in blood pressure. In hyperthyroidism reduced systemic
vascular resistance and increased blood volume lead to an enhanced preload,
which, in association with reduced afterload, improved contractility, as well as
increased beta-adrenergic activity, results in isolated systolic hypertension
based on enhanced stroke volume and cardiac output. In contrast, hypothyroidism
causes increased systemic vascular resistance in association with decreased
arterial compliance resulting in elevated diastolic blood pressure. Therefore in
the evaluation of arterial hypertension secondary hypertension based on thyroid
disease should always be considered, especially given the fact that blood
pressure changes in the course of thyroid dysfunction are usually reversible upon
adequate treatment of hypo- or hyperthyroidism.

Ann Endocrinol (Paris). 2011 Sep;72(4):296-303.
Arterial hypertension and thyroid disorders: What is important to know in
clinical practice?
Mazza A, Beltramello G, Armigliato M, Montemurro D, Zorzan S, Zuin M, Rampin L,
Marzola MC, Grassetto G, Al-Nahhas A, Rubello D.
Department of Internal Medicine, Santa Maria della Misericordia Hospital, via Tre
Martiri 140, 45100 Rovigo, Italy.
This review describes the pathogenic mechanisms of blood pressure (BP) regulation
and long-term control in thyroid disorders. Variations from the euthyroid status
affect virtually all physiological systems but the effects on the cardiovascular
system are particularly pronounced. Thyroid disorders induce several hemodynamic
changes leading to elevated BP as a consequence of their interaction with
endothelial function, vascular reactivity, renal hemodynamic and
renin-angiotensin system. However, in thyroid disorders, the regulation of BP and
the development and maintenance of variable forms of arterial hypertension (HT)
are different. Hyperthyroidism results in an increased endothelium-dependent
responsiveness secondary to the shear stress induced by the hyperdynamic
circulation, and contributes to reduce vascular resistance. Conversely,
hypothyroidism is accompanied by a marked decrease in sensitivity to sympathetic
agonists with an increase of peripheral vascular resistance and arterial
stiffness. Furthermore in animal models, hypothyroidism reduces the
endothelium-dependent and nitric oxide-dependent vasodilatation. HT due to
thyroid disorders is usually reversible with achievement of euthyroidism, but in
some cases pharmacological treatment for BP control is required. In
hyperthyroidism, β-blockers are the first-choice treatment to control BP but when
they are contraindicated or not tolerated, ACE-inhibitors or calcium-channel
blockers (CCB) are recommended. Hypothyroidism is a typical low rennin HT form
showing a better antihypertensive response to CCB and diuretics; indeed in
hypothyroidism a low-sodium diet seems further to improve BP control. Randomized
clinical trials to compare the efficacy on BP control of the antihypertensive
treatment in thyroid disorders are needed.

Anesthesiology. 1997 Jul;87(1):102-9.
Positive inotropic and lusitropic effects of triiodothyronine in conscious dogs with pacing-induced cardiomyopathy.
Jamall IN, Pagel PS, Hettrick DA, Lowe D, Kersten JR, Tessmer JP, Warltier DC.
Department of Medicine (Division of Cardiovascular Diseases), Medical College of Wisconsin, Milwaukee 53226, USA.
BACKGROUND:
The effects of triiodothyronine (T3) on systemic hemodynamics, myocardial contractility (preload recruitable stroke work slope; Mw), and left ventricular (LV) isovolumic relaxation (time constant; tau) were examined before and after the development of pacing-induced cardiomyopathy in conscious dogs.
METHODS:
Dogs (n = 8) were chronically instrumented for measurement of aortic and LV pressure, dP/dtmax, subendocardial segment length, and cardiac output. Dogs received escalating doses (0.2, 2.0, and 20.0 mg/kg, intravenous) of T3 over 5 min at 1-h intervals, and peak hemodynamic effects were recorded 10 min after each dose and 24 h after the final dose. Dogs were then continuously paced at 220-240 beats/min for 21 +/- 2 days. Pacing was temporarily discontinued after the development of severe LV dysfunction, and administration of T3 was repeated.
RESULTS:
T3 produced immediate and sustained (24 h) increases (P < 0.05) in Mw and dP/dtmax in dogs before the initiation of pacing, consistent with a positive inotropic effect. No changes in tau occurred. Rapid ventricular pacing over 3 weeks increased baseline heart rate (sinus rhythm) and LV end-diastolic pressure, decreased mean arterial and LV systolic pressures, and caused LV systolic (decreases in Mw and dP/dtmax) and diastolic (increases in tau) dysfunction. T3 caused immediate and sustained increases in Mw (63 +/- 7 during control to 82 +/- 7 mmHg after the 2 mg/kg dose) and decreases in tau (65 +/- 8 during control to 57 +/- 6 ms after the 20 mg/kg dose), indicating that this hormone enhanced myocardial contractility and shortened LV relaxation, respectively, in the presence of chronic LV dysfunction. In contrast to the findings in dogs with normal LV function, T3 did not affect heart rate and calculated indices of myocardial oxygen consumption and reduced LV end-diastolic pressure (27 +/- 3 during control to 20 +/- 2 mmHg after the 2 mg/kg dose) in cardiomyopathic dogs.
CONCLUSIONS:
The findings indicate that T3 produces favorable alterations in hemodynamics and modest positive inotropic and lusitropic effects in conscious dogs with LV dysfunction produced by rapid LV pacing.

Can J Physiol Pharmacol. 2006 Aug-Sep;84(8-9):935-41.
Effects of triiodo-thyronine on angiotensin-induced cardiomyocyte hypertrophy:
reversal of increased beta-myosin heavy chain gene expression.
Wang B, Ouyang J, Xia Z.
Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan
430071, P.R. China.
Thyroid hormone-induced cardiac hypertrophy is similar to that observed in
physiological hypertrophy, which is associated with high cardiac contractility
and increased alpha-myosin heavy chain (alpha-MHC, the high ATPase activity
isoform) expression. In contrast, angiotensin II (Ang II) induces an increase in
myocardial mass with a compromised contractility accompanied by a shift from
alpha-MHC to the fetal isoform beta-MHC (the low ATPase activity isoform), which
is considered as a pathological hypertrophy and inevitably leads to the
development of heart failure. The present study is designed to assess the effect
of thyroid hormone on angiotensin II-induced hypertrophic growth of
cardiomyocytes in vitro. Cardiomyocytes were prepared from hearts of neonatal
Wistar rats. The effects of Ang II and 3,3',5-triiodo-thyronine (T3) on
incorporations of [3H]-thymine and [3H]-leucine, MHC isoform mRNA expression, PKC
activity, and PKC isoform protein expression were studied. Ang II enhanced
[3H]-leucine incorporation, beta-MHC mRNA expression, PKC activity, and
PKCepsilon expression and inhibited alpha-MHC mRNA expression in cardiomyocytes.
T3 treatment prevented Ang II-induced increases in PKC activity, PKCepsilon, and
beta-MHC mRNA overexpression and favored alpha-MHC mRNA expression. Thyroid
hormone appears to be able to reprogram gene expression in Ang II-induced cardiac
hypertrophy, and a PKC signal pathway may be involved in such remodeling process.

J Med 1997;28(5-6):319-24
Reduced serum T3 level in a patient with nodular goiter and cardiac myxoma.
Sumino H; Kanda T; Kobayashi I; Sakamoto H; Sato K; Sakamaki T; Fukuda T; Ichikawa S; Nagai R
We report the unusual case of an 87-year-old woman with cardiac myxoma and adenomatous goiter. She exhibited slight elevations of serum interleukin-6 (IL-6), but levels of thyroid hormones such as T3, free T3 and free T4 were all abnormally low. Interleukin-6 may potentiate the alteration of thyroid metabolism.

J Clin Endocrinol Metab. 2013 May;98(5):E862-6.
The dynamic pituitary response to escalating-dose TRH stimulation test in
hypothyroid patients treated with liothyronine or levothyroxine replacement
therapy.
Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS.
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive,
Bethesda, MD 20892-1613, USA.
CONTEXT: A recent trial showed that 1:3 μg:μg liothyronine (L-T3) substitution
for levothyroxine (L-T4) achieving near-identical TSH levels resulted in a
significant decrease in weight and cholesterol levels with no appreciable changes
in cardiovascular parameters, suggesting a differential peripheral response to
the therapy.
OBJECTIVE: We characterized the pituitary-thyroid axis in hypothyroid patients
receiving equivalent doses of L-T3 or L-T4 by escalating-dose TRH stimulation
test.
DESIGN: A secondary analysis of a L-T3 vs L-T4 therapy trial was performed.
SETTING: The study was conducted at the National Institutes of Health.
PATIENTS: Thirteen patients were studied.
INTERVENTIONS: Escalating-dose (5, 15, and 200 μg) TRH stimulation test on both
treatment arms.
MAIN OUTCOME MEASURES: Study outcomes were peak serum TSH concentration (Cmax),
time to peak TSH concentration (Tmax), area under the curve from 0 to 60 minutes
(AUC₀₋₆₀) after TRH injection.
RESULTS: Thirteen patients aged 51.2 ± 8.29 years completed escalating-dose TRH
stimulation test. No significant difference between L-T3 and L-T4 treatments was
observed in TSH Cmax or area under the curve. L-T4 resulted in a small but
significantly shorter Tmax compared to L-T3 (3.5 ± 0.73 min on 200 μg TRH dose, P
< .03). In addition, 5 μg TRH dose compared to 200 μg resulted in a shorter Tmax
on both treatment arms (6.9 ± 0.59 min L-T3, 4 ± 0.3 min L-T4; P = .0002).
CONCLUSIONS: The assessment of the dynamic pituitary response to escalating doses
of TRH confirms that substitution of L-T3 for L-T4 on a 1:3 ratio achieves a
near-identical degree of pituitary euthyroidism. Furthermore, the data suggest
that lower doses of TRH might provide clinically relevant information of
thyrotroph function, particularly when investigating partial pituitary
insufficiency states.

Intern Med. 2012;51(21):3009-15.
A low fT3 level as a prognostic marker in patients with acute myocardial
infarctions.
Zhang B, Peng W, Wang C, Li W, Xu Y.
Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University
School of Medicine, China.
Comment in
Intern Med. 2013;52(5):645.
Intern Med. 2013;52(5):647.
OBJECTIVE: To investigate the association between low free triiodothyronine (fT3)
levels and the severity and prognosis of patients with acute myocardial
infarction.
METHODS: A total of 501 patients with acute myocardial infarctions were enrolled
in our study. The circulating levels of thyroid hormones and clinical parameters
were assayed. The patients were categorized into either the low fT3 group or the
normal fT3 group according to the fT3 level on admission. All patients underwent
a follow-up for 10±2 months for mortality from any cause and the occurrence of
any adverse major cardiac events (MACE).
RESULTS: There were 171 patients in the low fT3 group (fT3<3.5 pmol/L) and 330
patients in the normal fT3 group (≥3.5 pmol/L). During the follow-up period, 33
patients died (6.6%) and the overall survival rates were 86.0% and 97.3% in
patients with a low fT3 level and a normal fT3 level, respectively. The rates of
MACE were 66.7% and 45.5% in the patients with and those without low fT3 levels,
respectively. Using a multivariable Cox proportional hazards model, the fT3 level
was found to be the most important predictor of cumulative death and MACE (hazard
ratio

---

for death: 0.142, p<0.001 and HR for major adverse cardiac events:
0.748, p=0.007). A Kaplan-Meier analysis revealed that those patients with low
fT3 levels had higher rates of MACE and death.
CONCLUSION: A low fT3 level, a common phenomenon in patients with acute
myocardial infarctions, is a strong predictor of short-term and long-term poor
prognoses in patients with acute myocardial infarctions.

J Clin Endocrinol Metab. 2012 Jul;97(7):2256-71.
Combination treatment with T4 and T3: toward personalized replacement therapy in
hypothyroidism?
Biondi B, Wartofsky L.
Department of Clinical and Molecular Endocrinology and Oncology, University of
Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy. [email protected]
CONTEXT: Levothyroxine therapy is the traditional lifelong replacement therapy
for hypothyroid patients. Over the last several years, new evidence has led
clinicians to evaluate the option of combined T(3) and T(4) treatment to improve
the quality of life, cognition, and peripheral parameters of thyroid hormone
action in hypothyroidism. The aim of this review is to assess the physiological
basis and the results of current studies on this topic.
EVIDENCE ACQUISITION: We searched Medline for reports published with the
following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid,
guidelines, treatment, deiodinases, clinical symptoms, quality of life,
cognition, mood, depression, body weight, heart rate, cholesterol, bone markers,
SHBG, and patient preference for combined therapy. The search was restricted to
reports published in English since 1970, but some reports published before 1970
were also incorporated. We supplemented the search with records from personal
files and references of relevant articles and textbooks. Parameters analyzed
included the rationale for combination treatment, the type of patients to be
selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy
on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral
parameters of thyroid hormone action.
EVIDENCE SYNTHESIS: The outcome of our analysis suggests that it may be time to
consider a personalized regimen of thyroid hormone replacement therapy in
hypothyroid patients.
CONCLUSIONS: Further prospective randomized controlled studies are needed to
clarify this important issue. Innovative formulations of the thyroid hormones
will be required to mimic a more perfect thyroid hormone replacement therapy than
is currently available.

Am J Cardiol. 2012 Jul 15;110(2):234-9.
Association of serum triiodothyronine with B-type natriuretic peptide and severe
left ventricular diastolic dysfunction in heart failure with preserved ejection
fraction.
Selvaraj S, Klein I, Danzi S, Akhter N, Bonow RO, Shah SJ.
Division of Cardiology, Department of Medicine, Northwestern University Feinberg
School of Medicine, Chicago, Illinois, USA.
There are well-documented changes in thyroid hormone metabolism that accompany
heart failure (HF). However, the frequency of thyroid hormone abnormalities in HF
with preserved ejection fraction (HFpEF) is unknown, and no studies have
investigated the association between triiodothyronine (T(3)) and markers of HF
severity (B-type natriuretic peptide [BNP] and diastolic dysfunction [DD]) in
HFpEF. In this study, 89 consecutive patients with HFpEF, defined as symptomatic
HF with a left ventricular ejection fraction >50% and a left ventricular
end-diastolic volume index <97 ml/m(2), were prospectively studied. Patients were
dichotomized into 2 groups on the basis of median T(3) levels, and clinical,
laboratory, and echocardiographic data were compared between groups. Univariate
and multivariate linear regression analyses were performed to determine whether
BNP and DD were independently associated with T(3) level. We found that 22% of
patients with HFpEF had reduced T(3). Patients with lower T(3) levels were older,
were more symptomatic, more frequently had hyperlipidemia and diabetes, and had
higher BNP levels. Severe (grade 3) DD, higher mitral E velocity, shorter
deceleration time, and higher pulse pressure/stroke volume ratio were all
associated with lower T(3) levels. T(3) was inversely associated with log BNP (p
= 0.004) and the severity of DD (p = 0.039). On multivariate analysis, T(3) was
independently associated with log BNP (β = -4.7 ng/dl, 95% confidence interval
-9.0 to -0.41 ng/dl, p = 0.032) and severe DD (β = -16.3 ng/dl, 95% confidence
interval -30.1 to -2.5 ng/dl, p = 0.022). In conclusion, T(3) is inversely
associated with markers of HFpEF severity (BNP and DD). Whether reduced T(3)
contributes to or is a consequence of increased severity of HFpEF remains to be
determined.
Copyright © 2012 Elsevier Inc. All rights reserved.

Basic Res Cardiol. 2012;107(6):307. doi: 10.1007/s00395-012-0307-z. Epub 2012 Oct
26.
Increased afterload induces pathological cardiac hypertrophy: a new in vitro
model.
Hirt MN, Sörensen NA, Bartholdt LM, Boeddinghaus J, Schaaf S, Eder A, Vollert I,
Stöhr A, Schulze T, Witten A, Stoll M, Hansen A, Eschenhagen T.
Department of Experimental Pharmacology and Toxicology, University Medical Center
Hamburg-Eppendorf and DZHK, Germany.
Increased afterload results in 'pathological' cardiac hypertrophy, the most
important risk factor for the development of heart failure. Current in vitro
models fall short in deciphering the mechanisms of hypertrophy induced by
afterload enhancement. The aim of this study was to develop an experimental model
that allows investigating the impact of afterload enhancement (AE) on
work-performing heart muscles in vitro. Fibrin-based engineered heart tissue
(EHT) was cast between two hollow elastic silicone posts in a 24-well cell
culture format. After 2 weeks, the posts were reinforced with metal braces, which
markedly increased afterload of the spontaneously beating EHTs. Serum-free,
triiodothyronine-, and hydrocortisone-supplemented medium conditions were
established to prevent undefined serum effects. Control EHTs were handled
identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine
(PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes
in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or
PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining.
Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene
program, increased glucose consumption, and increased mRNA levels and
extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs
exhibited reduced contractile force and impaired diastolic relaxation directly
after release of the metal braces. These deleterious effects of afterload
enhancement were preventable by endothelin-A, but not endothelin-B receptor
blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce
pathological cardiac remodeling with reduced contractile function and increased
glucose consumption. The model will be useful to investigate novel therapeutic
approaches in a simple and fast manner.

Heart and hormones (May, 2013 newsletter)



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.

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.

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.

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.

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.

(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.)

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.

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.

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.

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).

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).

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.

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.

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.

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).

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).

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).

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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).

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.

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).

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.



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[messtafarian]

More from Dr. Peat:

I know a few healthy seeming people whose TSH is in the range of 0.2 to 0.7, but most of them are in the range of 0.0001 to 0.1. Low temperature and pulse rate and those uterine problems just don't occur in hyperthyroidism, and as you saw in the articles, hypothyroidism is a common cause of high blood pressure. I have known people whose thyroid nodules didn't shrink with just thyroxine, but did shrink quickly with T3.