In the past, the overemphasis on hyperthyroidism and thyrotoxicosis and heart diseases has made many doctors think that only excess T3 and T4 is bad for the heart.
We finally have an article that focuses on the real cause-effect relationships on the opposite end of the thyroid dysfunction spectrum: HYPOthyroidism.
This May 2019 article co-authored by three women and two men from Portugal emphasizes the research on hypothyroidism, especially T3 deficiency, and its adverse effects on ischemic heart disease.
In the past, I’ve written a prior campaign blog article about thyroid hormones and the cardiovascular system, but none of those articles I reviewed make me as delighted as this one.
Thank you, dear Madalena von Hafe, João Sergio Neves, Catarina Vale, Marta Borges-Canha, and Adelino Leite-Moreira, for this information-packed and paradigm-shifting article.
I just about fell off my computer chair when I did a word count on the article for “T3” and found 107 references to the queen of all thyroid hormones! 107! My fingers type with great speed as I write this and my heart leaps for joy! (no, not a palpitation, not an arrythmia….)
von Hafe et al’s article even goes beyond that to focus on ways in which T3 therapy can reduce cardiovascular risk and promote healing.
I could hardly believe my eyes when I read “The use of levothyroxine requires the preservation of peripheral deiodinase activity to convert T4 into the active hormone T3. Administration of T3 may be a better option [than T4] in patients with impaired conversion.”
Apparently the article was not funded by the makers of a levothyroxine drug.
Oh, oh, yes, and there’s more … von Hafe and team also talked about a randomized study on T3 therapy in patients with acute myocardial infarction whose T3 falls low, and the exciting things it’s discovering.
“This study showed that T3 therapy is safe and improves regional dysfunction in patients with STEMI and NTIS. The results reveal the absence of major or minor side effects induced by T3 treatment such as arrhythmias and increased heart rate.”
The article then went on to review further recent research publications showing the benefits of T3 treatment in Non-thyroidal illness syndrome (NTIS), a.k.a. Low T3 syndrome.
Ah, but I run ahead of myself out of enthusiasm for the treasures in this final section on treatment!
Why am I so enthusiastic?
This is a personal topic for me, as a person whose cardiovascular distress was dismissed in Emergency three times. My three year history of chronic low T3 (and my wild, unreasonably antibody-inflated TSH in spite of high-normal FT4) was the only shocking thing in my lab results back in 2016 when I suffered. My treatment with T3 hormone put a stop to my horrors and restored my health. So this article applies a further healing salve to me.
I also hope von Hafe’s article offers healing and vindication to a certain courageous Emergency physician from Digby, Nova Scotia whose license to treat thyroid was taken away because he knew and practiced the things this article teaches… Dr. Ron Matsusaki.
Our GPs and our Emergency physicians need to take a lesson from this article about the significance of lower T3 levels in patients presenting with adverse cardiovascular symptoms and signs.
von Hafe, M., Neves, J. S., Vale, C., Borges-Canha, M., & Leite-Moreira, A. (2019). The impact of thyroid hormone dysfunction on ischemic heart disease. Endocrine Connections. https://doi.org/10.1530/EC-19-0096
THYROID HORMONE CONVERSION
How refreshing to see the very first section of this article focus on the thyroid hormone receptor as the site of T3 action on tissues and organs throughout the human body.
This is followed by the importance of T3 secretion and T4-T3 conversion.
Prior articles on thyroid hormone and the heart have tended to talk generically about “thyroid hormone” (abbreviated TH) as if T4 and T3 were Siamese twins, a singular entity in which T3 was indistinguishable from T4.
Not anymore. Here we have T3 put in its proper place: “T3 is 20 times more potent than T4, making T3 the biologically active hormone of the thyroid axis.”
Two sentences later we also have the acknowledgement that not all T4 is destined to become T3. The deiodinases, they explain, “are also responsible for converting THs into inactive isomers such as reverse T3 (rT3) and 3,3-diiodothyronine (T2).
THE EFFECTS OF THYROID HORMONES ON THE CARDIOVASCULAR SYSTEM
That’s their heading, and it’s great. It acknowledges the cause-effect relationship between thyroid hormones and this system, rather than the indirect risk associations with pituitary TSH hormone.
In this section, the abbreviation “TH” for “thyroid hormone” is used as a synonym for T3, because “The major effects of THs on the myocardium are mediated by T3.”
What’s the word count on ” THs ” (with spaces) in this article? 63. Add 63 references to the 107 references to T3 hormone and you have an article that mentions T3 directly or indirectly 170 times. (I often do word counts to find references to T3 in articles, and this is unparalleled.)
Here is a list of all the things T3 does, using the verbs they chose for its many actions:
(Just skim the opening verbs if you are not interested in the technical details.)
- stimulates nearly all of the transporters and ion channels involved in calcium myocardial fluxes
- enhance[s] calcium uptake and release
- stimulate[s] both diastolic myocardial relaxation and systolic myocardial contraction
- upregulate α-MHC and downregulate β-MHC
- increase[s] resting heart rate, cardiac contractility and venous tone almost immediately, increasing cardiac preload and cardiac output
- increases myocardial sensitivity to the adrenergic system by increasing the number of adrenergic membrane receptors
- decreases systemic vascular resistance through vascular smooth-muscle relaxation
- decreases renal perfusion and leads to renin-angiotensin-aldosterone axis activation
- relax[es] vascular smooth muscle [which] may lead to an increase in cardiac oxygenation
- increases metabolic and oxygen consumption, thereby enhancing the release of vasodilatory mediators
- induce[s] a rapid vascular relaxation that is mediated by NO produced by vascular smooth-muscle and endothelial cells
- ha[s] a proangiogenic effect, stimulating arteriolar growth in the normal heart as well as after myocardial infarction
- induce[s] angiogenesis
- modulate[s] metalloproteinases (MMP), increasing MMP 1 and 2 as well as collagen gene expression; consequently, they may have an important impact on the extracellular matrix of the heart
- [has an] antifibrotic effect … a reduction in scar size
- increas[es] mitochondrial mass, respiration, oxidative phosphorylation, enzyme activity and mitochondrial protein synthesis
- may reduce cardiomyocyte loss … reduced myocyte apoptosis
… The list goes on. I can’t go on. It would get boring to the non-cardiologists reading this. You get the point.
The T3 hormone is immensely powerful and it does a truckload of essential functions in the cardiovascular system.
As you can see, cardiologists have no reason to harp on TSH-associations when they have so many direct and positive effects of thyroid hormone (mainly T3) to focus on.
Their next section focuses on the harmful effects of hyperthyroidism, but I appreciate the fact their section on hypothyroidism, which follows, is twice its length.
CARDIOVASCULAR EFFECTS OF HYPOTHYROIDISM
Most of the harms of hypothyroidism (low T3 and T4 thyroid hormones, not elevated TSH) reverse or block the long list of good things from happening in the cardiovascular system.
One of the first things they narrate is the hypothyroid patient’s journey to heart failure: “The hypothyroid state results in lower heart rate and decreased myocardial contraction and relaxation, with prolonged systolic and early diastolic time intervals, culminating in advanced stages of heart failure.”
The only unfortunate thing about this section is that their paragraph openings have defined hypothyroidism by TSH above reference and thyroid hormones below it.
However, they atone for this traditional nod to TSH-ism by including WITHIN this section on hypothyroidism a discussion of the Nonthyroidal illness syndrome (NTIS).
This is revolutionary!
It has long been the practice to place a discussion of NTIS in an entirely separate category to say that it is NOT hypothyroidism.
This article, by its structure, finally admits that a low T3 syndrome IS a form of hypothyroidism.
I know, how could a syndrome characterized by a low thyroid hormone (T3) not be hypothyroidism? Um, because TSH is not elevated and often patients exhibit no “clinical signs” of hypothyroidism while their bodies suffer a T3 deficit. Decades of endocrinology have seen Low T3 syndrome as “not hypothyroidism.” This article corrects that error.
Their Figure 2 explains the “Main changes in cardiovascular system with low T3 levels in nonthyroidal illness.”
Another revolutionary factor in this article’s discussion is that the figure includes factors that take a time to develop, like “insulin resistance” and “atherosclerosis.”
It’s revolutionary because NTIS has often been associated with “critical illness” — acute crises, not chronic and long-term syndromes. This common misconception has made it seem like you come down with low T3 like you come down with a flu, and you recover just as quickly and easily. NO, it’s not always that fast, and not that benign, according to this article.
Next, the article correctly focuses on the “aberrant expression of deiodinases” in NTIS. This is the process by which T3 becomes depleted, and remains depleted, in tissues.
Too often I have read articles that present NTIS as a benign and natural phenomenon and Reverse T3 (RT3) as an inert molecule that happens to build up in illness and not get cleared out fast enough.
But this article’s authors admit that Deiodinase Type 3, which destroys thyroid hormone and leaves in its wake RT3 hormone buildup, can be pathological.
Yes, they actually use the word “pathological.”
“The main mechanism seems to involve reduced activity of the deiodinases that convert T4 to T3 and an increase in deiodinase D3 that converts T4 to rT3 …
Recent studies show that expression of D3 is increased in some pathological contexts in a cell-specific manner, which are cancer, cardiac hypertrophy, myocardial infarction, chronic inflammation or critical illness.”
They talk about the process by which this pathological overexpression of D3 and chronic inflammation and hypoxia lead to “local cardiac hypothyroidism” — in which the heart has even less T3 than you can measure floating around in the bloodstream.
In low T3 syndrome, by definition, blood T3 is already lower than the body needs it to be, and this article says T3 is even lower in the heart muscle itself.
At this point, I can imagine one of the article reviewers forced von Hafe and her team to insert a single sentence which seems out of place: “In most conditions, NTIS seems to be an adaptive, compensatory and beneficial response, decreasing energy consumption in response to inflammation during various critical illnesses.” Fine. They nodded their head to the benign thing “NTIS seems to be” to other people who read this.
Then, two sentences later, the emphasis shifts back to the dark side of NTIS:
“Increased rT3 may be considered a predictor of both short- and long-term mortality in ischemic heart disease (10). NTIS is often associated with depressed myocardial function and is be a strong predictor of mortality in patients with heart disease, both in acute and chronic conditions.”
THE IMMENSE IMPACT OF THYROID HORMONE DYSFUNCTION
“Myocardial ischemia is a major cause of mortality and morbidity worldwide,” is their opening statement.
Therefore, “An understanding of the mechanisms of interaction between THs [Thyroid hormones] and their receptors is crucial to assess their impact in myocardial ischemia.”
They cite the finding that “5–35%” of patients with acute coronary syndrome have NTIS.
What’s more, “Patients with ST-elevation myocardial infarction (STEMI) and alterations in thyroid function have almost a 3.5-fold increased risk of major adverse cardiac events, including cardiogenic shock and death, compared with patients with STEMI and no thyroid disorder.”
Wow. A 3.5-fold increased risk of adverse events. Like death. When STEMI is combined with thyroid disorder.
Low T3 levels and/or high Reverse T3 at the time of the acute myocardial infarction has long-term effects on recovery 6 months later. The 1-year mortality increases.
And what about all the follow-up surgeries that attempt to help the patient and repair the heart? Those surgeries put patients at risk of Low T3 again and again.
“NTIS is reported in 50–75% of patients after cardiac surgery and some authors consider this as a poor prognostic factor and a predictor of mortality.”
Heart surgery is an expensive, delicate procedure. We want it to succeed.
Therefore, studies are looking into “pretreatment” with T3 before going into surgery. “The interest in the role of THs [Thyroid hormones] in cardioprotection is increasing.”
The subsequent sections, therefore, lead into the climax of the article, which discusses thyroid hormone treatments.
THYROID HORMONE TREATMENT
There is no evidence of thyroid pharma prejudice here.
All thyroid hormones are on the table, from levothyroxine to T3 to other thyro-mimetic compounds that target thyroid hormone receptors.
The only thyroid pharmaceutical not mentioned explicitly by name is desiccated thyroid, but as you will see, it is mentioned indirectly, sneakily …
The section provides both the pro and the con of levothyroxine, and both the pro and con of T3 therapy.
The negative side of levothyroxine, again, is that the body needs to convert it to T3, which is less likely to happen in patients with poor T4-T3 conversion, which is common in heart failure and other heart conditions.
The negative side of using T3, of course, relates to risk of overdose.
T3’s very potency, its ability to heal, is its Achilles heel.
But far, far more is written here about the studies that show T3’s benefits, alone or in combination with T4, both in human trials and in animal studies.
Even children — yes children! — are participants in studies of T3 pretreatment for cardiac surgery.
“The results of a double-blind, randomized placebo-controlled clinical trial suggested that 0.4 mg/kg taken orally once a day for 4 days before surgery may provide protection against myocardial IRI during cardiac surgery in children by increasing HSP70 and MHC-α expression, inducing pharmacological ischemic preconditioning.”
Is 0.4 mg/kg a typo? That’s 400 micgrograms per kilogram of a thyroid drug!
I checked the article cited, an article by Zhang et al, 2018. The trial group of children took ” 0.4 mg/kg (trial group) (taken orally, once a day) for 4 days before surgery.”
What did the children take?
Here’s the Chinese authors’ defense of their choice of T4 and T3 thyroid hormone molecule source, in their own words:
“Considering that postoperative decline of serum T3 and T4 is common in children undergoing cardiac surgery with CPB, oral preparation of thyroid hormones used in this study is thyroid tablet including T3 and T4. Thyroid tablet is made from thyroid gland of sheep or pig, and is frequently applied for treatment of hypothyroidism in children.”
Breathe easier: 0.4 mg per kg would be is a very low dose if it’s a child. Zhang et al recruited children aged 3 to 12 years. According to a random internet page, a 3-year old weighs about 14.2 kg, so they’d get a dose of 5.68 mg per day. A 12-year-old weighs about 41.5 kg, so they’d get a dose of 16.6 mg/day. An adult full thyroid replacement of desiccated thyroid can be about 120 mg/day. It is not that frightening anymore.
Back to von Hafe et al’s article.
In another research study they review, even a low daily dose of T3, a mere 1.2 micrograms per 100g in rats, confers benefits to their healing from MI, and the practical applications to humans are profound: “Low-dose THs might offer a suitable treatment option after myocardial infarction in patients who are intolerant to aerobic exercise training.”
The section on treatment ends with an important point — tiny changes in thyroid hormone levels WITHIN the normal reference range are significant!
“Evidence suggests that the hypothyroid tissue state may be present independent of normal circulating levels of THs. Therefore, it is important to identify a good biomarker of tissue hypothyroid-like state in order to treat patients effectively.”
What matters more than the reference range boundary is whether or not tissues like the heart muscle and blood vessels are getting enough T3. Even tiny doses can help.
The sun shines favorably on the treatment of lower T3 in von Hafe’s article, even within reference range, given its important benefits to the heart and the protection and healing it offers during the crises of acute coronary events, when T3 is at risk.
“The results are promising so far; experimental and clinical studies demonstrate that THs can limit ischemic injury, attenuate cardiac remodeling, and improve hemodynamics.”
The final brief paragraph trumpets the declarations doctors need to hear.
First of all: Low thyroid hormone levels are the main issue when it comes to cardiovascular tissue.
It’s not about TSH-based definitions of hypothyroidism, nor is it about a certain magic number or reference boundary. “Low” thyroid hormone means “low” from the perspective of the body, not from the perspective of some arbitrary statistical population reference range boundary.
“It is now recognized that even subtle changes in TH levels can lead to adverse effects in the cardiovascular system. …
Experimental and clinical evidence suggests a close link between low TH levels and poor prognosis in ischemic heart disease. This condition should therefore be regarded as a cardiovascular risk factor.”
Notice this — Low thyroid hormone levels, not necessarily high TSH, “should therefore be regarded as a cardiovascular risk factor.”
I’ll end with this quotation from the conclusion. Its final words should echo in the grateful, awe-struck silence. That pause of silence ought to anticipate a round of intellectual applause, followed by action. We need action to change medical policies, practices, and research agendas in this direction:
“Accordingly, TH replacement therapy may yield improvements in lipid profiles, potentially reversing myocardial dysfunction and preventing the progression to heart failure. TH replacement treatment exhibits anti-ischemic and cardioprotective effects, acting as a promising target for ischemic heart disease. Moreover, subclinical hypothyroidism treatment and nonthyroidal illness syndrome constitute topics garnering increased interest; recent studies suggest that therapy with physiological doses of T3 are safe and provide beneficial effects on ischemic heart disease.”
- Tania S. Smith