This comment is by my colleague Prof Johannes Dietrich. It shows how frequent are cardiac problems even with mild hypothyroidism.
Mild thyroid disorders can cause severe heart problemsby Ruhr-Universitaet-Bochum Types and mechanisms of thyroid hormone signaling. T4 is a prohormone with respect to genomic signaling, but a true fast-acting hormone regarding type 4 action (which is inhibited by the iodothyroacetate TETRAC). Genomic action (type 1, type 2 and mitochondrial signaling) occurs on a slow time scale, whereas non-genomic effects (type 3 and type 4 signaling) represent a fast response (A). Thyroid hormone receptors (THR) usually act as heterodimers. Without thyroid hormone bound they block the transcription together with corepressors. Iodothyronines displace the corepressors and stimulate gene expression together with coactivators (B). Tissue specific distributions of THRs further contribute to the diversity of signaling patterns in the organism (C). AF-1, activation function 1; AF-2, activation function 2; D2, type 2 deiodinase; DBD, DNA-binding domain; HAT, histone acetyl-transferase; HDAc, histone deacetylase; LBD, ligand-binding domain; RXR, retinoid X receptor; TRE, thyroid-hormone response element Frontiers in Cardiovascular Medicine (2022). DOI: 10.3389/fcvm.2022.942971 It has been known for more than 200 years that severe thyrotoxicosis may lead to cardiac arrhythmia (irregular heartbeat), one of the major reasons for sudden cardiac death. However, the risk associated with mild hyperthyroidism or hypothyroidism hasn't been understood so far. A systematic evaluation of 32 studies with 1.3 million participants shows that even slight deviations in thyroid function can increase the risk of serious cardiovascular diseases."This puts our understanding of the interaction between the thyroid gland and the heart on a new footing and might pave the way to personalized preventive care," says associate professor Dr. Johannes Dietrich from the Department of Medicine at St Josef Hospital, Clinic of Ruhr University Bochum, Germany (RUB). The researchers published their work in Frontiers in Cardiovascular Medicine.For the study, the heart and hormone researchers at RUB collaborated with a clinician scientist/hormone specialist affiliated with Tan Tock Seng Hospital, the Nanyang Technological University's Lee Kong Chian School of Medicine and Duke-NUS Medical School in Singapore.How should mild thyroid dysfunctions be treated?Today, overt thyroid dysfunction is recognized as an established risk factor for major adverse cardiovascular events (MACE). However, the situation remained equivocal in mild thyroid dysfunction."Whereas in some studies, minimal elevations of thyroid hormones and even high-normal concentrations within the reference range for healthy people predicted an increased risk for sudden cardiac death, other studies hadn't shown such a correlation," explains Johannes Dietrich. Until very recently, the jury was therefore still out on whether to treat those with subclinical forms of hyperthyroidism and hypothyroidism.In order to gain a better understanding, a fresh systematic review by the international team analyzed the results of 32 studies on this issue. In a pooled statistical evaluation with consecutive meta-analysis, the researchers found both subclinical hypothyroidism and subclinical hyperthyroidism to predict the risk for cardiovascular mortality. In particular, serum concentrations of the free thyroid hormone T4 (FT4) correlated directly with the probability of cardiac death and other adverse cardiovascular events.Two different patterns"The results suggest that cardiovascular risk increases continuously with the FT4 concentration, whereas a complex U-shaped risk relationship exists with the concentration of the controlling hormonethyrotropin, i.e. TSH," elaborates Johannes Dietrich. This dualism may be explained by two different patterns of thyroid-mediated arrhythmia.In one form ("dyshomeostatic type"), primary thyroid disease directly elevates the concentration of thyroid hormones and thereby increases the cardiovascular risk. In the other form ("allostatic type"), genetic factors, chronic stress and psychological strain increase the set point of the regulatory circuit between the pituitary gland and the thyroid gland, so that the indirectly increased FT4 concentration also promote arrhythmia."The results of this study might pave the way to a personalized preventive strategy for heart outcomes," conclude the authors. "Moreover, thyroid function might serve as a biomarker for the respective mechanism of origin in patients harboring cardiac arrhythmia, helping to tailor individually optimized medication regimen."
More information: Patrick Müller et al, Minor perturbations of thyroid homeostasis and major cardiovascular endpoints—Physiological mechanisms and clinical evidence, Frontiers in Cardiovascular Medicine (2022). DOI: 10.3389/fcvm.2022.942971
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Very interesting Diogenes. For those of us that don't convert well our T4 to T3. Adding some even very small amount of T3 for our hearts well being is very beneficial and important. The heart has a large receptor sight for T3. On T4 sole after my TT I was having very frightening experiences with palpitations. After adding small dose T3 to my T4 mix my palpitations thankfully stopped. Thank you for sharing great posts with us.
I don’t get it (sorry I got a D in A Level Biology) so is he saying over range FT4 correlates to increased cardio risk?
How does someone with sub-clinical or hypothyroidism get over range FT4? Especially before diagnosis, surely if I show this to my doc she’ll tell me she wants my T4 lower in range? Leaving me under medicated ? Doesn’t sound like good news? Have I misread it?
Although I like the ‘pave the way for individualised treatment’ that but jumped off the page 💚
A lot of detail but I am not clear what the conclusions are to draw - or perhaps they are not clear either yet. I had read before that uncontrolled hypo eg TSH >10-15 risks heart issues and that is easy to follow. Here the issue seems to be more about other levels eg t4. When he talks about “slight deviations in thyroid function “ what aspects is he referring to …
on reading again it seems to be looking more at patients who are sub-clinical so I suspect have a higher tsh of say 4-9 or a somewhat low one ie borderline hypo or hyper and whether not being treated matters.
If this is correct they are querying the existing NHS wisdom say to not dose T4 until tsh >10 (certainly this applies at my local surgery) unless other major symptoms exist eg goitre
Also to address hyper issues due to high heart rates and risk to heart health
On that basis I agree with them and it does all make sense - but it is not for my circumstances I think who has addressed this issue with hormone supplements
How does someone with sub-clinical or hypothyroidism get over range FT4? .... they didn't
.... it was looking at both subclinical/ hyper and subclinical/ hypo ... it's the subclinical hyper ones who had the high T4 , not the subclinical hypo's
..... they were referring to fT4 levels within the normal range (but high up).
Higher T4 did = more risk.
but at first glance i think ? these studies were looking at risks to un-treated subclinical hyper/ hypo's not taking thyroid hormone.
ie. Sub clinical hyper ~TSH below range/ fT4 in range.
and Sub-clinical hypo ~ TSH above range/ fT4 in range.
In treated hypo's taking levo , the relationship between TSH and fT4 is changed a bit , and so their fT4 level might not necessarily have exactly the same association with risks as seen in subclinical hyper's .
Well i think so anyway ... but am getting out of my depth, so i'll shut up . lol
I think I may beg to differ here with you - they are referring to hyper and not hypo patients who have high FT4 who are way over the range and use this test to get consider medicine to reduce FT4 - they need to reduce racing hearts and heart health
I am not sure someone who is over medicated will need thyroid hormone - perhaps some drugs to reduce the levels. The supplementation I think was. relating to those with hypo. My other query is what drives the heart problems - you can get high T4 with thyroid medications and should we be worried if T4 is well over range even if TSH is not quite in the right range.
I am no expert really and I think the writer is confusing topics especially for hypo patients taking thyroxine.
You will read these comments and probably feel you have covered the bases so no major need to reply
I think you have posted this twice, perhaps you could get an administrator to remove one copy.
This is very advanced stuff, a bit beyond me and no doubt well beyond many of the endocrinologists we encounter.
Johannes pointed out that there is a correlation between cardiac failure and fT4. T4 has non-genomic effects that cause cardiac problems (and promote cancer). This effect is much reduced or absent with T3. He points out that Tetrac blocks this action.
We can take two points from this. 1. Higher levels of T4 (even within the reference interval) are undesirable. 2. The evidence is that replacing some of the T4 with T3 will reduce these risks.
You are right this paper doesn't explicitly state that using T3 will reduce the cardiac risks. I guess I can wriggle out of the problem by saying that if you substitute a little T3 for T4 you are lowering fT4 levels and so reducing the risks
I posted about this a while ago healthunlocked.com/thyroidu... . I looked at the statistical links because the science is very deep and difficult, about non-genomic receptors at the cell membrane.
Thanks for this link, that is a very useful thread, and now I follow the logic. Much appreciated, this will influence my upcoming review after 8 weeks of 25mcg Levo increase to 100mcg. It also explains the GP comments about FT4 recently when I was discussing my (mistaken) aim to be higher in range (in the hope I’m a good converter). I will prepare my notes and references, she does like to know the source and ‘someone I met online’ is the incorrect response 😬
Sorry jimh11 that's still not correct. The research (from that snippet) doesn't state that replacing T4 with T3 (or lowering T4) will reduce heart disease at all!
They have found a correlation between t4 and heart disease, but it's important to note they haven't found a causation. That might be scope for the next research as this paper does bring up the question. But from this research there's no evidence that lowering T4 will have the effect of lowering heart disease. It just says that if T4 happens to be low in your body, heart disease risk is lower too. And it's very possible (for example) that there's another shared variable which causes both high T4 and high cardiac risk.
You are correct and I am using a degree of guesswork. The question is whether heart disease causes higher T4 levels with little or no effect on T3. This is unlikely but not impossible. The other point is these studies were on the whole prospective, they measured TSH, fT4 and then looked at future cardiac disease. It is known that T4 is a hormone for the integrin ανβ3 receptor which has roles in cancer and cardiac disease (although I have no knowledge of this role). So, there is a possible mechanism but we are currently at the stage where we know there is an association and have some non-conclusive evidence of causation. On the balance of probability I feel we should avoid levothyroxine monotherapy as it probably increases the risk of cardiac disease and does increase cancer mortality. There are also other reasons to advocate levothyroxine / liothyronine combination therapy as it gives better symptom resolution in some cases.
I thought the basic link to heart disease was that low thyroid levels = high cholesterol and adding Thyroixine raises thyroid levels and reduces cholesterol levels and risk of heart attack and stroke.
I suspect the link to cancer is the breakdown of the immune function with hashinotos, although with correct diet and throcine dosing auto immune function can be improved.
I am very unsure anyone can claim a strong link for cancer for those who are on top of their thyroid management care routine - for some like me who only have a Levo option if is best for me not to dwell on it - I have a close relative of 99 who is well and using Levo for past 40 years
The Grahame Leese study I cite in my post below shows the relative cardiac (and osteoporosis) risks for people on levothyroxine (based on TSH). Too much levothyroxine causes cardiac problems as does too little.
The cancer risk is due to effects on the integrin αvβ3 receptor, T4 activates this receptor, I posted about it here healthunlocked.com/thyroidu... .
The study Diogenes is posting about has a diagram that shows the integrin αvβ3 receptor . I haven’t read this paper yet.
I left out one point. It is of course possible that there is a common factor that causes cardiac problems and higher T4. I think this is unlikely. We really need a trial, this would have to be very large scale and over a long time. I feel that the best approach is to make combination therapy the default approach and monitor the outcomes. This would be better than selecting a trial group of e.g. 200,000 and monitoring them over e.g 30 years because if T4 is more harmful there will be a lot of harm done over the next 30 years. It's a question of playing the odds, something that happens in medicine all the time.
Well lowering T4 and increasing T3 by taking NDT stopped my heart problems and many others in here say t3 has helped their heart health. We can’t all be imagining it. I’m with jim111 on this matter I don’t believe in any shared variable doing it all. Why did our once functioning thyroid give us both hormones in health I’m sure it’s because we needed them.
I know we're all different but I was wondering if you could share where your free t3 and free t4 hover on the range to make your heart happiest? I'd appreciate if you could share the ranges as well. Also, how much are you taking of the ndt? I'm always curious to see the numbers of those that struggle with palpitations, tachycardia or Afib.
Ive dealt with chest pain , palpitations and tachycardia and low t3 for many yrs.
I’m afraid I haven’t got many results on NDT I felt so well on it I couldn’t see the need for them. I might have two somewhere provably on line needing a ling forgotten password to get to them. I have my levo ones somewhere in a file.if I happen upon them I’ll made the effort to post them. I did put one lot up on here a long time ago from the levo horror days.
Thnxs for taking the time to respond. I read your reply where you shared your experience. We have similarities of having thyroid atrophy and excruciating chest pain. I can recall the amount of time I would hunch over clutching my chest from the pain. It was a mixture of being stabbed and squeezed at the heart. If you end up finding the labs with the free t3 and free t4 with ndt, I would ever be grateful if you share them on here or pm.
In untreated SCHypo, there seems to be no relationship between FT3 and TSH. In SCHyper, there can be. So I would think that for SCHypo, FT4 will tell you more than FT3. The relationship with FT4 as regards cardiac problems seems to be the driver, but a high FT4 won't surely diagnose one person as prone to cardiac problems: it's still only an increased probability. There are of course all sorts of confounders, in which pituitary sensitivity is one. There is a need to define cause and effect and I think the Dietrich team are on the case.
I have always had low heart rate 52/54. Sinus Bradychardia. Put it down to hypothyroid, but I do keep fit & exercise regularly. However, in last 2 years (I am 59), I also have 'Left Axis Deviation'...which I didnt have a clue what that meant! Discovered at private medical, no way GP would test for stuff like this. I have had elderly parents with Atrial fibrillation, but thought this was age related.I feel best on 125mcg levo, plus vits D & B12, and magnesium I find is brilliant. Helps me sleep, avoid constipation, and helps with aching joints. If my levo dose is lowered, I feel depressed, suffer with constipation, and feel generally rotten.
Sometimes I do get some slight palpitations, but I drink coffee!...Must change to decaff!
I trust you make progress with your L.A.D. My GP arranged electro- and echocardiograms earlier this year, just on my reported symptoms. However, there's been no followup thyroid testing, perhaps because I said I'd arranged a private test to catch my symptoms when they were likely to be at their worst. The echo showed dilated left atrium. My heart rate during that was 60bpm and I'm regularly below 50bpm despite very little exercise. In my 20s, as a long distance cyclist, it was below 40bpm and didn't increase appreciably during most hyper phases (word finding problem just then: could only think of appreciatively). The cardiologist I had went abroad for a professorship, but seemed to have little interest in thyroid issues, though he did arrange fT3 testing when told I was taking desiccated thyroid extract as well as levothyroxine.
I haven't even thought about the cardiac issues, but would you please be able to simplify this to a layman's ability to understand this. I think this may have been something my late mother would have benefited from knowing. Thank you!
In SCHypo, as an average, FT4 is lower than healthy controls by about 1.5pmol/L with FT3 not affected. In SCHyper, FT4 is on average 1.5 pmol/L higher than healthy controls. So it looks as if adverse situations can occur, possibly by increased supply of T3 to the heart which is unwanted and can have implications. It is NOT the case that heart problems suddenly show themselves when someone becomes definitely hyperthyroid, but there is a lesser but finite possibility well before this (heralded by higher FT4 in the reference range).
Initially, I now believe I was mildly hyperthyroid (many symptoms) although at the time I just thought I was a high energy person. In my 30’s I got sudden and quite severe heart pains that had me grovelling on the floor clutching my chest in agony, they happened about 3 or 4 times over a week or so at which point I though I’d see the doc if it happened again, but they disappeared as mysteriously as they came. I got another bout in my 40’s for which I sought help. I had an abnormal ECG and was sent for a stress exercise test at the hospital which also showed problems in one chamber, but I was told it was just something women of my age got and was of no consequence. By my 50’s the pains began to get much worse but of course of I though they were just my lot in life as a woman because of what that consultant had told me. I had so many health issues by now it was embarrassing traipsing In and out of the doctors. I though I was a crazy hypochondriac and gave up on seeking help I just silently suffered them. I became so ill I made one last desperate attempt to get someone to do a thyroid function test. I was lucky to get a really decent GP who did listen despite me being almost unintelligible by that point, my heart pains were really bad by this time. The test came back hyperthyroid but I was convinced I was hypothyroid as I was no longer the person with boundless energy I felt exhausted most of the time with occasional energetic episodes and I wasn’t at all right. They did another test soon after that one which came back very overtly hypothyroid. The thyroid hormones were sky high to rock bottom. My diagnosis was atropic autoimmune thyroiditis. I was treated with a tiny dose of Levothyroxine and just pulled through The heart pains became even worse on Levothyroxine with no respite after two years with TSH optimised but very low t3 and high end of range t4. I used to think I was going to drop dead of a heart attack when those pains hit. I found they soon disappeared on NDT. A huge relief. I wonder if this presentation of thyroid disorder is more likely to lead to heart problems. I believe it is more common than one might think but there is a scarcity of literature about it and it’s lumped with Hashimotos but it is quite distinct from it and more akin to Graves’ disease in its initial stages indicated by the type of antibody involvement. Would this ever be take into account in the research by Prof Deitrich, might not a study of this hybrid form of thyroid disease be quite revealing?
An additional comment which I hope is helpful. It seems that both thyroid hormone action and T4 can have adverse cardiac effects. i.e. too much T3, T4 or too little are harmful and too much T4 is harmful. It is difficult to disentangle these two effects.
I like this study academic.oup.com/jcem/artic... led by Graham Leese. It shows the effects of under and over treatment with levothyroxine (as determined by TSH). Figure 2 gives a very nice easy to follow presentation. It shows that in spite of the effects of too much hormone (and too much T4) the harmful effects of hypothyroidism are greater. It also uses a logarithmic scale for TSH which is a better way of reporting it.
Some chance! If the current medical malpractice is anything to go by, the odds of being treated correctly are next to nil! My (former) GP recognised the relationship between my heart disease and being mistreated for my hypothyroidism but could do nothing about it. The entire thing is a sick joke practiced on us by the NHS!
I went 2 years with under-active thyroid before it was finally diagnosed in my mid 30’s, terrible gastric problems and other hypothyroid symptoms, in hospital twice for tests but no diagnosis of cause. It got to a point where I felt that I was slowly dying, managed to get appointment with brilliant GP told him all the symptoms and straight away he said ‘I think you may have a thyroid problem ‘ and he was right. At age 51 I suffered a sudden heart attack and had emergency triple coronary bypass. No family history of cardiac problems, I didn’t suffer from high blood pressure or high cholesterol and cardiologist said that I wasn’t a typical candidate for coronary artery disease. I had always suspected a possible link to 2 years of illness with undiagnosed hypothyroidism and subsequent cardiac problems years later. My wife who also has hypothyroidism was over medicated with Levothyroxine for over a year and only discovered because she developed Atrial Fibrillation, which eventually cleared up after five years of correct levels of Levothyroxine and meds for Atrial Fibrillation. She no longer suffers from AF. I must admit that I have little faith in the NHS to provide effective treatments for thyroid problems, I mean in our health region the lab won’t even test T4 levels and will only test TSH, my GP requested T4 test in the past and it was rejected as inappropriate request. When discussing with a now retired GP, he said that years ago they would test T3 and would prescribe Levothyroxine accordingly but patients would still present with inadequate T3 levels which couldn’t be understood so it was decided presumably by NICE to just test TSH. I said to that GP that T4 is not adequately converted to T3 in some (probably many) hypothyroid patients so just increasing T4(Levothyroxine) would not adequately treat it. It seems the NHS want the cheapest solution to testing and treating thyroid problems which I suspect leads to many other health problems in many patients throughout their lives and ends up costing the NHS more in the long run by not adequately treating hypothyroidism and hyperthyroidism.
It shows just how complex the problem is of dealing with a primary organ like the thyroid that interacts with so many bodily functions; the hypothamus, the pituitary, the adrenals and the heart and the stomach, is it any wonder that the medical business chooses the line of least resistance? And once more, I wonder what the role of a male-dominated medical 'profession' plays in the issue given that 70% of thyroid sufferers are female, that it's been neglected for so long.
Yes NHS treatments seem to be protocol driven and at times seems to be based on keeping the cost down. As you say thyroid problems are complex to treat properly and think that’s why there isn’t world class treatment in U.K. NHS.
I'll leave this here in case anyone can make sense of it.
My wife, who from 2013 has a history of AF and ablations and has been on T3 only since about 2014, is convinced that her heart is more stable nowadays after gradually increasing her T3 (only) dose from 30 to 50+. Her GP was flabbergasted when she told him and he has been very supportive in increasing her T3 prescription over the years. She just cannot tolerate T4. We're wondering whether the T4, which she was taking from 2010 onwards after a hemithyroidectomy, was the cause of her AF. Initially she was started on 25T4 (!) and that was increased in steps of 25 until she got to 100T4. By that time, she felt really unwell and we went to see Dr P who said T4 was the problem and recommended T4/T3 therapy. Things started to improve when she started on T3/T4 therapy, initially 75T4/20T3 and eventually 0T4/30T3, recommended by an NHS consultant incidentally.
Thank you for post - It is always helpful to be made aware of other research - and it’s conclusions - I have highish T4 and breathless since Covid - and blood results show inflammation in the body - So I appreciate you letting me know High T4 may be a marker for heart issues - I will relay this to my doctor with not much hope it will concern her - thanks
diogenes Can you pls spare some time to provide some feedback. At my lowest, my free t3 was below range for many months and now it's much better thanks to God. Since high free t3 in the company of high normal free t4 is risky, around what number should my free t4 be to play it safe for my heart????
I've started the process of a slight reduction but would like to have an idea of where to aim for the free t4. I know it's all hypothetical but curious to know what % would put me back in a non risky area.
Btw thank you for making the time out of your life to respond
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Mathematical modeling of the pituitary-thyroid feedback loop: role of a TSH-T3-shunt and sensitivity analysis
